Tricyclic heterocycles as fgfr inhibitors

ABSTRACT

The present disclosure relates to tricyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR enzyme and are useful in the treatment of FGFR-associated diseases such as cancer.

FIELD

The present disclosure relates to tricyclic heterocycles, andpharmaceutical compositions of the same, that are inhibitors of theenzyme FGFR and are useful in the treatment of FGFR-associated diseasessuch as cancer.

SEQUENCE LISTING

This application contains a Sequence Listing that has been submittedelectronically as an ASCII text file named “Sequence_Listing.txt.” TheASCII text file, created on Jun. 6, 2022, is 1 kilobyte in size. Thematerial in the ASCII text file is hereby incorporated by reference inits entirety.

BACKGROUND

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005,16, 139-149). Aberrant activation of this pathway either throughoverexpression of FGF ligands or FGFR or activating mutations in theFGFRs can lead to tumor development, progression, and resistance toconventional cancer therapies. In human cancer, genetic alterationsincluding gene amplification, chromosomal translocations and somaticmutations that lead to ligand-independent receptor activation have beendescribed (Reviewed in Knights and Cook, Pharmacology & Therapeutics,2010, 125, 105-117; Turner and Grose, Nature Reviews Cancer, 2010, 10,116-129). Large scale DNA sequencing of thousands of tumor samples hasrevealed that FGFR genes are altered in many cancers (Helsten et al.Clin Cancer Res. 2016, 22, 259-267). Some of these activating mutationsare identical to germline mutations that lead to skeletal dysplasiasyndromes (Gallo et al. Cytokine & Growth Factor Reviews 2015, 26,425-449). Mechanisms that lead to aberrant ligand-dependent signaling inhuman disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities. Therefore, development of inhibitors targeting FGFR may beuseful in the clinical treatment of diseases that have elevated FGF orFGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, colorectal, endometrial,gastric, head and neck, kidney, lung, ovarian, prostate); hematopoieticmalignancies (e.g., multiple myeloma, acute myelogenous leukemia, andmyeloproliferative neoplasms); and other neoplasms (e.g., glioblastomaand sarcomas). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

There is a continuing need for the development of new drugs for thetreatment of cancer, and the FGFR inhibitors described herein helpaddress this need.

SUMMARY

The present disclosure is directed to compounds having Formula I:

or pharmaceutically acceptable salts thereof, wherein constituentvariables are defined herein.

The present disclosure is further directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present disclosure is further directed to methods of inhibiting anFGFR enzyme (e.g., an FGFR3 enzyme) comprising contacting the enzymewith a compound of Formula (I), or a pharmaceutically acceptable saltthereof.

The present disclosure is further directed to a method of treating adisease associated with abnormal activity or expression of an FGFRenzyme (e.g., an FGFR3 enzyme), comprising administering a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, to a patientin need thereof.

The present disclosure is further directed to compounds of Formula (I)for use in treating a disease associated with abnormal activity orexpression of an FGFR enzyme (e.g., an FGFR3 enzyme). The presentdisclosure is further directed to the use of compounds of Formula (I) inthe preparation of a medicament for use in therapy.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to said patient a compound of Formula (I), orpharmaceutically acceptable composition thereof.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to the patient a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with another therapy or therapeutic agent as describedherein.

DETAILED DESCRIPTION Compounds

In one aspect, the present disclosure provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R^(X) is selected from methyl and Cl;

Cy¹ is selected from

R¹ is selected from CH₂OH, CH₂CH₂OH, CHF₂, NH₂, and CH₃;

R² is selected from ethyl, —(C₁₋₄ alkyl)-OH, —(C₁₋₃ alkyl)-CN, (C₁₋₃alkyl)-C(O)NH₂, —(C₁₋₄ alkyl)-C(O)N(CH₃)₂, CH₂CH₂S(O)₂CH₃, and thefollowing groups:

R^(2A) is selected from CH₃, C(O)CH₃, C(O)CH₂OCH₃, and C(O)CH₂OH;

R^(2B) is selected from H, CN, CF₃, and C(O)N(CH₃)₂; and

R^(2C) is selected from H and F;

provided that the compound is not:

-   2-(2,6-Dichlorophenyl)-3-methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine,-   3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile,-   1-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,-   2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)acetonitrile,-   (2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol,-   2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol,-   (2-(2,6-Dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol,    or-   2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)ethan-1-ol.

In some embodiments, R^(X) is methyl.

In some embodiments, R^(X) is Cl.

In some embodiments, Cy¹ is Cy¹-1:

In some embodiments, Cy¹ is Cy¹-2:

In some embodiments, R¹ is selected from CH₂CH₂OH, CHF₂, and NH₂.

In some embodiments, R¹ is selected from CH₂OH and CH₂CH₂OH.

In some embodiments, R¹ is CH₂OH. In some embodiments, R¹ is CH₂CH₂OH.In some embodiments, R¹ is CHF₂. In some embodiments, R¹ is NH₂. In someembodiments, R¹ is CH₃.

In some embodiments, R² is selected from ethyl, CH(CH₃)CH₂OH,CH₂CH(CH₃)OH, CH(CH₃)CH₂CN, C(CH₃)₂CN, CH(CH₃)CN, C(CH₃)₂C(O)NH₂,CH₂C(O)N(CH₃)₂, and the following groups:

In some embodiments, R² is selected from ethyl, —(C₁₋₄ alkyl)-OH, —(C₁₋₃alkyl)-CN, (C₁₋₃ alkyl)-C(O)NH₂, —(C₁₋₄ alkyl)-C(O)N(CH₃)₂, andCH₂CH₂S(O)₂CH₃.

In some embodiments, wherein R² is selected from ethyl, CH(CH₃)CH₂OH,CH₂CH(CH₃)OK, CH(CH₃)CH₂CN, C(CH₃)₂CN, CH(CH₃)CN, C(CH₃)₂C(O)NH₂, andCH₂C(O)N(CH₃)₂.

In some embodiments, R² is selected from the following groups:

In some embodiments, R² is selected from the following groups:

In some embodiments, R² is selected from the following groups:

In some embodiments, R² is selected from the following groups:

In some embodiments, R^(2A) is CH₃.

In some embodiments, R^(2A) is selected from C(O)CH₃, C(O)CH₂OCH₃, andC(O)CH₂OH.

In some embodiments, R^(2B) is selected from CN, CF₃, and C(O)N(CH₃)₂.

In some embodiments, R^(2B) is H.

In some embodiments, R^(2C) is F.

In some embodiments, R^(2C) is H.

In one aspect, the present disclosure provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R^(X) is selected from methyl and Cl;

Cy¹ is selected from

R¹ is selected from CH₂OH, CH₂CH₂OH, CHF₂, NH₂, and CH₃;

R² is selected from ethyl, —(C₁₋₄ alkyl)-OH, —(C₁₋₃ alkyl)-CN, (C₁₋₃alkyl)-C(O)NH₂, —(C₁₋₄ alkyl)-C(O)N(CH₃)₂, CH₂CH₂S(O)₂CH₃, and thefollowing groups:

R^(2A) is selected from CH₃, C(O)CH₃, C(O)CH₂OCH₃, and C(O)CH₂OH;

R^(2B) is selected from H, CN, CF₃, and C(O)N(CH₃)₂; and

R^(2C) is selected from H and F;

provided that:

-   -   (a) when R¹ is CH₃, then R² is other than        tetrahydro-2H-pyran-4-yl; and    -   (b) when R¹ is CH₂OH and R^(X) is Cl, then R² is other than        CH₂CN, CH₂CH₂CN, CH₂C(CH₃)₂₀H, C(CH₃)₂ CH₂OH, CH₂CH₂OH,        CH₂CH₂S(O)₂CH₃, and

In one aspect, the present disclosure provides compounds of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein R^(X), R¹, and R²are as defined herein.

In one aspect, the present disclosure provides compounds of Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein R^(X), R¹, and R²are as defined herein.

In some embodiments, provided herein is a compound of Formula I wherein:

R^(X) is selected from methyl and Cl;

Cy¹ is selected from

R¹ is selected from CH₂OH, CH₂CH₂OH, CHF₂, NH₂, and CH₃;

R² is selected from ethyl, CH(CH₃)CH₂OH, CH₂CH(CH₃)OH, CH(CH₃)CH₂CN,C(CH₃)₂CN, CH(CH₃CN, C(CH₃)₂C(O)NH₂, CH₂C(O)N(CH₃)₂ and the followinggroups:

R^(2A) is selected from CH₃, C(O)CH₃, C(O)CH₂OCH₃, and C(O)CH₂OH;

R^(2B) is selected from H, CN, CF₃, and C(O)N(CH₃)₂; and

R^(2C) is selected from H and F.

In some embodiments, provided herein is a compound of Formula I wherein:

R^(X) is selected from methyl and Cl;

Cy¹ is selected from

R¹ is selected from CH₂CH₂OH, CHF₂, and NH₂;

R² is selected from ethyl, —(C₁₋₄ alkyl)-OH, —(C₁₋₃ alkyl)-CN, (C₁₋₃alkyl)-C(O)NH₂, —(C₁₋₄ alkyl)-C(O)N(CH₃)₂, CH₂CH₂S(O)₂CH₃, and thefollowing groups:

R^(2A) is selected from CH₃, C(O)CH₃, C(O)CH₂OCH₃, and C(O)CH₂OH;

R^(2B) is selected from H, CN, CF₃, and C(O)N(CH₃)₂; and

R^(2C) is selected from H and F.

In some embodiments, provided herein is a compound of Formula I wherein:

R^(X) is CH₃;

Cy¹ is selected from

R¹ is selected from CH₂OH, CH₂CH₂OH, CHF₂, NH₂, and CH₃;

R² is selected from ethyl, —(C₁₋₄ alkyl)-OH, —(C₁₋₃ alkyl)-CN, (C₁₋₃alkyl)-C(O)NH₂, —(C₁₋₄ alkyl)-C(O)N(CH₃)₂, CH₂CH₂S(O)₂CH₃, and thefollowing groups:

R^(2A) is selected from CH₃, C(O)CH₃, C(O)CH₂OCH₃, and C(O)CH₂OH;

R^(2B) is selected from H, CN, CF₃, and C(O)N(CH₃)₂; and

R^(2C) is selected from H and F.

In some embodiments, provided herein is a compound of Formula I which isselected from:

-   (2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol;-   5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)nicotinonitrile;-   5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)picolinonitrile;-   4-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)picolinonitrile;-   (2-(2,6-Dichlorophenyl)-9-(1-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol;-   (4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)phenyl)(morpholino)methanone;-   ((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)methanone;-   1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzyl)piperazin-1-yl)-2-hydroxyethan-1-one;-   1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzyl)piperazin-1-yl)ethan-1-one;-   1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)piperazin-1-yl)-2-hydroxyethan-1-one;-   (2-(2-Chloro-6-methylphenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol;-   5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)-N,N-dimethylpicolinamide;-   (3-(4-(2-(2,6-Dichlorophenyl)-3-methylimidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methyl-1H-1,2,3-triazol-4-yl)methanone;-   (3-(4-(2-(2,6-Dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(2-methyl-2H-tetrazol-5-yl)methanone;-   (2-(2,6-Dichlorophenyl)-9-(1-ethyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol;-   2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile;-   2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile;-   1-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propan-2-ol;-   2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide;-   1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one;-   1-(4-(4-(2-(2-Chloro-6-methylphenyl)-3-(hydroxymethyl)imidazo[2,1-][A1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethan-1-one;-   1-(4-(2-(2-Chloro-6-methylphenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;-   3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)butanenitrile;-   (R)-2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propan-1-ol;-   (2-(2,6-Dichlorophenyl)-9-(1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-][1,6]naphthyridin-3-yl)methanol;-   3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran    1,1-dioxide;-   1-(3-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)azetidin-1-yl)-2-methoxyethan-1-one;-   2-(2,6-Dichlorophenyl)-3-(difluoromethyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-][1,6]naphthyridine;-   2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)acetonitrile;-   2-(2,6-Dichlorophenyl)-3-(difluoromethyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-][1,6]naphthyridine;-   2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)ethan-1-ol;-   2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile;-   2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide;-   2-(2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)ethan-1-ol;    and-   2-(2,6-Dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-][1,6]naphthyridin-3-amine,

or a pharmaceutically salt of any of the aforementioned.

It is further appreciated that certain features of the disclosure, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment Conversely,various features of the disclosure which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the disclosure are disclosed in groups or in ranges. It isspecifically intended that the disclosure include each and everyindividual subcombination of the members of such groups and ranges.

For example, the term “C₁₋₆ alkyl” is specifically intended toindividually disclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, andC₆ alkyl.

For compounds of the disclosure in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. A single divalent substituent,e.g., oxo, can replace two hydrogen atoms.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. An alkyl group formally corresponds to analkane with one C—H bond replaced by the point of attachment of thealkyl group to the remainder of the compound. In some embodiments, thealkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples ofalkyl moieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, means a saturated divalent linkinghydrocarbon group that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkylene group contains from 1 to 4carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.Examples of alkylene moieties include, but are not limited to, chemicalgroups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene,1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present disclosure. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out bymethods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzylamine (e.g., S and R forms,or diastereomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the disclosure have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the disclosure also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the disclosure also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium. One or moreconstituent atoms of the compounds of the disclosure can be replaced orsubstituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted. The term is also meant to refer to compounds of thedisclosure, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated. When in thesolid state, the compounds described herein and salts thereof may occurin various forms and may, e.g., take the form of solvates, includinghydrates. The compounds may be in any solid state form, such as apolymorph or solvate, so unless clearly indicated otherwise, referencein the specification to compounds and salts thereof should be understoodas encompassing any solid state form of the compound.

In some embodiments, the compounds of the disclosure, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of thedisclosure. Substantial separation can include compositions containingat least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, at least about 97%,or at least about 99% by weight of the compounds of the disclosure, orsalt thereof. Methods for isolating compounds and their salts areroutine in the art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present disclosure also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the non-toxic saltsof the parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentdisclosure can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography—mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); NIS (N-iodosuccinimide); nM (nanomolar); NMR(nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM(picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphoryl chloride);RP-HPLC (reverse phase high performance liquid chromatography); s(singlet); SEM (2-trimethylsilylethoxymethyl); t (triplet or tertiary);TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet oftriplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the disclosure can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the disclosure can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of Formula I can be prepared via the synthetic route asoutlined in Scheme 1.

Compounds of formula S-10 can be prepared via the synthetic route asoutlined in Scheme 1. Treatment of commercially available compound S-1with an appropriate reagent, such as phosphoryl chloride (POCl₃), atelevated temperature can afford the compound S-2. Chloride displacementof compound S-2 via nucleophilic substitution with aqueous ammonia atelevated temperature can deliver compound S-3. Condensation of compoundS-3 with compounds of formula S-4 (Hal is a halide, such as Cl, Br, orI) at elevated temperature can generate compounds S-5, which can undergoa reaction with an appropriate reagent, such as N-iodosuccinimide (NIS)or tert-butyl nitrite, to afford compounds S-6 (X is a substitutednitrogen, or a halide such as Cl, Br, or I). If X is a halide, compoundsS-6 can undergo a coupling reaction to an adduct of formula S-7, inwhich M is a boronic acid, a boronic ester or an appropriate reagent[e.g., M is B(OR)₂, Sn(Alkyl)₃, Zn-Hal, etc.], under standard Suzukicross-coupling conditions (e.g., in the presence of a palladium catalystand a suitable base) (Tetrahedron 2002, 58, 9633-9695), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst) (ACS Catalysis 2015, 5, 3040-3053), or standard Negishicross-coupling conditions (e.g., in the presence of a palladiumcatalyst) (ACS Catalysis 2016, 6, 1540-1552), to give a derivative offormula S-8. After coupling, if R¹ is a vinyl functional group it can beelaborated to a hydroxymethyl, hydroxyethyl, or difluoromethylsubstituent using known organic synthesis techniques. Introduction ofCy¹ can then be achieved by the coupling of compounds S-8 with an adductof formula S-9, using similar conditions as described for thepreparation of compounds S-8 from compounds S-6, to afford compounds offormula S-10.

Methods of Use

Compounds of the present disclosure can inhibit the activity of the FGFRenzyme. For example, compounds of the present disclosure can be used toinhibit activity of an FGFR enzyme in a cell or in an individual orpatient in need of inhibition of the enzyme by administering aninhibiting amount of one or more compounds of the present disclosure tothe cell, individual, or patient. Compounds of the present disclosurecan be used to inhibit activity of the FGFR3 enzyme in a cell or in anindividual or patient in need of inhibition of the enzyme byadministering an inhibiting amount of one or more compounds of thepresent disclosure to the cell, individual, or patient. Compounds of thepresent disclosure can be used to inhibit activity of the FGFR2 enzymein a cell or in an individual or patient in need of inhibition of theenzyme by administering an inhibiting amount of one or more compounds ofthe present disclosure to the cell, individual, or patient. Compounds ofthe present disclosure can be used to inhibit the activity of an FGFR3and an FGFR2 enzyme in a cell or in an individual or patient in need ofinhibition of the enzyme by administering an inhibiting amount of acompound of the disclosure to the cell, individual, or patient.

As FGFR inhibitors, the compounds of the present disclosure are usefulin the treatment of various diseases associated with abnormal expressionor activity of the FGFR enzyme or FGFR ligands. Compounds which inhibitFGFR will be useful in providing a means of preventing the growth orinducing apoptosis in tumors, particularly by inhibiting angiogenesis.It is therefore anticipated that compounds of the present disclosurewill prove useful in treating or preventing proliferative disorders suchas cancers. In particular, tumors with activating mutants of receptortyrosine kinases or upregulation of receptor tyrosine kinases may beparticularly sensitive to the inhibitors.

In certain embodiments, the disclosure provides a method for treating aFGFR-mediated disorder in a patient in need thereof, comprising the stepof administering to said patient a compound according to the invention,or a pharmaceutically acceptable composition thereof.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from adenocarcinoma, bladder cancer,breast cancer, cervical cancer, cholangiocarcinoma, colorectal cancer,endometrial cancer, esophageal cancer, gall bladder cancer, gastriccancer, glioma, head and neck cancer, hepatocellular cancer, kidneycancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreaticcancer, prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, and Burkett's lymphoma.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from hepatocellular cancer, bladdercancer, breast cancer, cervical cancer, colorectal cancer, endometrialcancer, gastric cancer, head and neck cancer, kidney cancer, livercancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer,gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, Burkett's lymphoma, glioblastoma, melanoma, and rhabdosarcoma.

In some embodiments, said cancer is selected from adenocarcinoma,bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma,endometrial cancer, gastric cancer, glioma, head and neck cancer, lungcancer, ovarian cancer, leukemia, and multiple myeloma.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from hepatocellular cancer, breastcancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lungcancer, prostate cancer, pancreatic cancer, testicular cancer, thyroidcancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterinecancer, and rhabdosarcoma.

A cancer characterized by an FGFR2 and/or FGFR3 alteration includesbladder cancers (FGFR3 mutation or fusion), cholangiocarcinoma (FGFR2fusion) and gastric cancer (FGFR2 amplification).

Compounds of the invention can be used to treat cancer patients withFGFR2/3 alterations, including mutations, fusion, rearrangement, andamplification. FGFR2/3 alterations were found in a subset ofcholangiocarcinoma, urothelial carcinoma, multiple myeloma, gastricadenocarcinoma, glioma, endometrial carcinoma, ovarian carcinoma,cervical cancer, lung cancer and breast cancer. Moreover, the compoundsof the invention can be used to target patients progressing on pan-FGFRinhibitor treatment due to acquirement of gatekeeper mutations(V555M/U/F/I in FGFR3, V564M/U/F/I in FGFR2). Also Compounds of theinvention can be used to treat cancer where FGFR2/3 signaling isinvolved in the resistance to other targeted therapies, for example, ithas the potential to overcome resistance to CDK4/6 inhibitors in ERpositive breast cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET), 8p11myeloproliferative syndrome), myelodysplasia syndrome (MDS), T-cellacute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-celllymphoma, adult T-cell leukemia, Waldenstrom's Macroglubulinemia, hairycell lymphoma, marginal zone lymphoma, chronic myelogenic lymphoma andBurkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma,lymphosarcoma, leiomyosarcoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellularcarcinoma, bronchial adenoma and pleuropulmonary blastoma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrinepancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma,lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer and anal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma) and urothelial carcinoma.

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors Exemplary nervous system cancers include cancers of the skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors, neuro-ectodermal tumors), and spinal cord(neurofibroma, meningioma, glioma, sarcoma), neuroblastoma,Lhermitte-Duclos disease and pineal tumors.

Exemplary gynecological cancers include cancers of the breast (ductalcarcinoma, lobular carcinoma, breast sarcoma, triple-negative breastcancer, HER2-positive breast cancer, inflammatory breast cancer,papillary carcinoma), uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers, tumors ofthe eye, tumors of the lips and mouth and squamous head and neck cancer.

The compounds of the present disclosure can also be useful in theinhibition of tumor metastases.

In addition to oncogenic neoplasms, the compounds of the invention areuseful in the treatment of skeletal and chondrocyte disorders including,but not limited to, achrondroplasia, hypochondroplasia, dwarfism,thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apertsyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosissyndromes. In some embodiments, the present disclosure provides a methodfor treating a patient suffering from a skeletal and chondrocytedisorder.

In some embodiments, compounds described herein can be used to treatAlzheimer's disease, HIV, or tuberculosis.

As used herein, the term “8p11 myeloproliferative syndrome” is meant torefer to myeloid/lymphoid neoplasms associated with eosinophilia andabnormalities of FGFR1.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with a compound described hereinincludes the administration of a compound described herein to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound described herein into a samplecontaining a cellular or purified preparation containing the FGFRenzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy. 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives.3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withcompounds described herein for treatment of FGFR-associated diseases,disorders or conditions, or diseases or conditions as described herein.The agents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Compounds described herein can be used in combination with one or moreother kinase inhibitors for the treatment of diseases, such as cancer,that are impacted by multiple signaling pathways. For example, acombination can include one or more inhibitors of the following kinasesfor the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. Additionally, the solid forms of the FGFR inhibitor asdescribed herein can be combined with inhibitors of kinases associatedwith the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (includingAkt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, compounds described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD47, CDK2, STING, ALK2,LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for thetreatment of diseases and disorders. Exemplary diseases and disordersinclude cancer, infection, inflammation and neurodegenerative disorders.

In some embodiments, compounds described herein can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, additional JAK1/2 andJAK1-selective, baricitinib or INCB39110), Pim kinase inhibitors (e.g.,LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors includingPI3K-delta selective and broad spectrum PI3K inhibitors (e.g., INCB50465and INCB54707), PI3K-gamma inhibitors such as PI3K-gamma selectiveinhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 andLY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, andMer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptorinhibitors, Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (Bortezomib, Carfilzomib),HDAC-inhibitors (panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family membersinhibitors (for example, bromodomain inhibitors or BET inhibitors, suchas OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g.,GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g.,INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat,NLG919 or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib),inhibitors of BTK such as ibrutinib, c-MET inhibitors (e.g.,capmatinib), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with chemotherapeuticagents, agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. Compounds described herein can also be usedin combination with a medical therapy such as surgery or radiotherapy,e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes.

Examples of suitable chemotherapeutic agents include any of: abarelix,abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole,aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine,bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide,bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfanintravenous, busulfan oral, calusterone, camptosar, capecitabine,carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine,dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib,dactinomycin, daunorubicin, decitabine, degarelix, denileukin,denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel,doxorubicin, droloxafine, dromostanolone propionate, eculizumab,enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lonafamib, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithranycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin,paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone,procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib,reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, tezacitabine, thalidomide,thioguanine, thiotepa, tipifamib, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard,valrubicin, vandetanib, vinblastine, vincristine, vindesine,vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4/6 kinaseinhibitors such as, for example, those described in WO 2006/056399 canbe used in combination with the treatment methods and regimens of thepresent disclosure for treatment of cancers and solid tumors. Otheragents such as therapeutic antibodies can be used in combination withthe treatment methods and regimens of the present disclosure fortreatment of cancers and solid tumors. The one or more additionalpharmaceutical agents can be administered to a patient simultaneously orsequentially.

The treatment methods as disclosed herein can be used in combinationwith one or more other enzyme/protein/receptor inhibitors therapies forthe treatment of diseases, such as cancer and other diseases ordisorders described herein. For example, the treatment methods andregimens of the present disclosure can be combined with one or moreinhibitors of the following kinases for the treatment of cancer: Akt1,Akt2, Akt3, BCL2, CDK2, CDK4/6, TGF-βR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma,delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4,flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB,TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1,EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK,FRK, JAK, ABL, ALK and B-Raf. Non-limiting examples of inhibitors thatcan be combined with the treatment methods and regimens of the presentdisclosure for treatment of cancer include an FGFR inhibitor (FGFR1,FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), anEGFR inhibitor (also known as ErB-1 or HER-1; e.g. erlotinib, gefitinib,vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), aVEGFR inhibitor or pathway blocker (e.g. bevacizumab, pazopanib,sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib,vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), a PARP inhibitor(e.g. olaparib, rucaparib, veliparib or niraparib), a JAK inhibitor(JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib, itacitinib(INCB39110), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50465 and INCB50797), aPI3K-gamma inhibitor such as PI3K-gamma selective inhibitor, a Piminhibitor (e.g., INCB53914), a CSF1R inhibitor, a TAM receptor tyrosinekinases (Tyro-3, Axl, and Mer), an adenosine receptor antagonist (e.g.,A2a/A2b receptor antagonist), an HPK1 inhibitor, a chemokine receptorinhibitor (e.g. CCR2 or CCR5 inhibitor), a SHP1/2 phosphatase inhibitor,a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, anangiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643), c-METinhibitors (e.g., capmatinib), an anti-CD19 antibody (e.g.,tafasitamab), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

In some embodiments, the treatment methods described herein are combinedwith administration of a PI3Kδ inhibitor. In some embodiments, thetreatment methods described herein are combined with administration of aJAK inhibitor. In some embodiments, the treatment methods describedherein are combined with administration of a JAK1 or JAK2 inhibitor(e.g., baricitinib or ruxolitinib). In some embodiments, the treatmentmethods described herein are combined with administration of a JAK1inhibitor. In some embodiments, the treatment methods described hereinare combined with administration of a JAK1 inhibitor, which is selectiveover JAK2.

Example antibodies that can be administered in combination therapyinclude, but are not limited to, trastuzumab (e.g., anti-HER2),ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g.,anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR),rituxan (e.g., anti-CD20), and antibodies directed to c-MET.

One or more of the following agents may be administered to a patient incombination with the treatment methods of the present disclosure and arepresented as a non-limiting list: a cytostatic agent, cisplatin,doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar,topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™(erlotinib), antibodies to EGFR, intron, ara-C, adriamycin, cytoxan,gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan,chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The treatment methods and regimens of the present disclosure can furtherbe used in combination with other methods of treating cancers, forexample by chemotherapy, irradiation therapy, tumor-targeted therapy,adjuvant therapy, immunotherapy or surgery.

Examples of immunotherapy include cytokine treatment (e.g., interferons,GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonalantibody, bispecific or multi-specific antibody, antibody drugconjugate, adoptive T cell transfer, Toll receptor agonists, RIG-Iagonists, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor, PI3Kδ inhibitor and the like.The compounds can be administered in combination with one or moreanti-cancer drugs, such as a chemotherapeutic agent. Examples ofchemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezomib, busulfan intravenous, busulfan oral, calusterone,capecitabine, carboplatin, carmustine, cetuximab, chlorambucil,cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine,dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin,decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, dromostanolone propionate, eculizumab, epacadostat,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinibmaleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, vorinostat, and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib,trilaciclib, lerociclib, and abemaciclib, and their pharmaceuticallyacceptable salts. Other example suitable CDK4/6 inhibitors includecompounds, and their pharmaceutically acceptable salts, as disclosed inWO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074,and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic in the treatment of cancer, andmay improve the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining treatment methods of the present disclosure withan additional agent.

The agents can be combined with Compound 1 and/or antibody that binds tohuman PD-1 or human PD-L1, or antigen-binding fragment thereof, of thepresent treatment methods in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the treatment methods ofthe disclosure where the dexamethasone is administered intermittently asopposed to continuously.

The treatment methods described herein can be combined with anotherimmunogenic agent, such as cancerous cells, purified tumor antigens(including recombinant proteins, peptides, and carbohydrate molecules),cells, and cells transfected with genes encoding immune stimulatingcytokines. Non-limiting examples of tumor vaccines that can be usedinclude peptides of melanoma antigens, such as peptides of gp100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The treatment methods described herein can be used in combination with avaccination protocol for the treatment of cancer. In some embodiments,the tumor cells are transduced to express GM-CSF. In some embodiments,tumor vaccines include the proteins from viruses implicated in humancancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBVand HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments,the treatment methods and regimens of the present disclosure can be usedin combination with tumor specific antigen such as heat shock proteinsisolated from tumor tissue itself. In some embodiments, the treatmentmethods described herein can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The treatment methods and regimens of the present disclosure can be usedin combination with bispecific macrocyclic peptides that target Fe alphaor Fe gamma receptor-expressing effectors cells to tumor cells. Thetreatment methods and regimens of the present disclosure can also becombined with macrocyclic peptides that activate host immuneresponsiveness.

In some further embodiments, the treatment methods of the disclosure arecombined with administration of other therapeutic agents to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant. The treatment methods and regimens of the present disclosurecan be used in combination with bone marrow transplant for the treatmentof a variety of tumors of hematopoietic origin.

When more than one pharmaceutical agents is administered to a patient,as discussed in any of the above embodiments, they can be administeredsimultaneously, separately, sequentially, or in combination (e.g., formore than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

In some embodiments, compounds described herein can be used incombination with immune checkpoint inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD %, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385),TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949),GITR (e.g., INCAGN1876) and CD137. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromA2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L 1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC50 less than 1 μM, less than 100 nM, less than10 nM or less than 1 nM in a PD-L 1 assay described in US PatentPublication Nos. US 20170107216, US 20170145025, US 20170174671, US20170174679, US 20170320875, US 20170342060, US 20170362253, and US20180016260, each of which is incorporated by reference in its entiretyfor all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,ipilumimab or AMP-224. In some embodiments, the anti-PD-1 monoclonalantibody is nivolumab or pembrolizumab. In some embodiments, theanti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1antibody is nivolumab.

In some embodiments, the anti-PD-1 monoclonal antibody is MGA012(retifanlimab). In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB(e.g. urelumab, utomilumab.

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD19, e.g., an anti-CD19 antibody. In some embodiments,the anti-CD19 antibody is tafasitamab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kdelta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7/8), TIGIT,CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immunecheckpoint molecule is a stimulatory checkpoint molecule selected fromCD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, theimmune checkpoint molecule is an inhibitory checkpoint molecule selectedfrom A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,TIGIT, and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab,avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab,spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001),camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224,AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736,FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316,CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333,MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, theinhibitor of PD-1 or PD-L1 is one disclosed in U.S. Pat. Nos. 7,488,802,7,943,743, 8,008,449, 8,168,757, 8,217, 149, or 10,308,644; U.S. Publ.Nos. 2017/0145025, 2017/0174671, 2017/0174679, 2017/0320875,2017/0342060, 2017/0362253, 2018/0016260, 2018/0057486, 2018/0177784,2018/0177870, 2018/0179179, 2018/0179201, 2018/0179202, 2018/0273519,2019/0040082, 2019/0062345, 2019/0071439, 2019/0127467, 2019/0144439,2019/0202824, 2019/0225601, 2019/0300524, or 2019/0345170; or PCT Pub.Nos. WO 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400, or WO 2011161699, which areeach incorporated herein by reference in their entirety. In someembodiments, the inhibitor of PD-L1 is INCB086550.

In some embodiments, the antibody is an anti-PD-1 antibody, e.g., ananti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224,JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042.In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, orsintilimab. In some embodiments, the anti-PD-1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.In some embodiments, the anti-PD-1 antibody is cemiplimab. In someembodiments, the anti-PD-1 antibody is spartalizumab. In someembodiments, the anti-PD-1 antibody is camrelizumab. In someembodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments,the anti-PD-1 antibody is toripalimab. In some embodiments, theanti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1antibody is AB122. In some embodiments, the anti-PD-1 antibody isAMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. Insome embodiments, the anti-PD-1 antibody is BGB-108. In someembodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, theanti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1antibody is LZM009. In some embodiments, the anti-PD-1 antibody isAK105. In some embodiments, the anti-PD-1 antibody is HLX10. In someembodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD1 antibody is SHR-1210. Other anti-canceragent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab,utomilumab). In some embodiments, the inhibitor of an immune checkpointmolecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonalantibody. In some embodiments, the anti-PD-L 1 monoclonal antibody isatezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736,atezolizumab (MPDL3280A; also known as RG7446), avelumab (MSB0010718C),FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301,BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, theanti-PD-L 1 antibody is atezolizumab, avelumab, durvalumab, ortislelizumab. In some embodiments, the anti-PD-L 1 antibody isatezolizumab. In some embodiments, the anti-PD-L 1 antibody is avelumab.In some embodiments, the anti-PD-L1 antibody is durvalumab. In someembodiments, the anti-PD-L1 antibody is tislelizumab. In someembodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments,the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody isKN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In someembodiments, the anti-PD-L 1 antibody is SHR-1316. In some embodiments,the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1antibody is A167. In some embodiments, the anti-PD-L1 antibody isSTI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. Insome embodiments, the anti-PD-L1 antibody is BGB-A333. In someembodiments, the anti-PD-L 1 antibody is MSB-2311. In some embodiments,the anti-PD-L 1 antibody is HLX20. In some embodiments, the anti-PD-L1antibody is LY3300054.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L 1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, U.S. Ser. No. 16/369,654(filed Mar. 29, 2019), and U.S. Ser. No. 62/688,164, or apharmaceutically acceptable salt thereof, each of which is incorporatedherein by reference in its entirety.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isMEDI9447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the agonist of an immune checkpoint molecule is aninhibitor of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469. In some embodiments, the agonist of an immune checkpointmolecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40Lfusion protein. In some embodiments, the anti-OX40 antibody isINCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998,BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein isMEDI6383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, the bispecificantibody binds to PD-1 and PD-L1. In some embodiments, the bispecificantibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments,the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments,the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.Inhibitors of arginase inhibitors include INCB1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with anti-hormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with FGFR inhibitors. These includeonartumzumab, tivantnib, and INC-280. Agents against Abl (or Bcr-Abl)include imatinib, dasatinib, nilotinib, and ponatinib and those againstAlk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds described herein. In some embodiments, the JAKinhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, compounds described herein can beadministered in the form of pharmaceutical compositions which refers toa combination of one or more compounds described herein, and at leastone pharmaceutically acceptable carrier or excipient. These compositionscan be prepared in a manner well known in the pharmaceutical art, andcan be administered by a variety of routes, depending upon whether localor systemic treatment is desired and upon the area to be treated.Administration may be topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufllation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, oral or parenteral. Methods for ocular delivery can includetopical administration (eye drops), subconjunctival, periocular orintravitreal injection or introduction by balloon catheter or ophthalmicinserts surgically placed in the conjunctival sac. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal, or intramuscular injection or infusion; orintracranial, e.g., intrathecal or intraventricular, administration.Parenteral administration can be in the form of a single bolus dose, ormay be, for example, by a continuous perfusion pump. Pharmaceuticalcompositions and formulations for topical administration may includetransdermal patches, ointments, lotions, creams, gels, drops,suppositories, sprays, liquids and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners and the like may benecessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, one or more compounds described herein incombination with one or more pharmaceutically acceptable carriers orexcipients. In making the compositions described herein, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders. In some embodiments, the composition issuitable for topical administration.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from, for example, about 5 mg to about 1000 mg, about 5 mg toabout 100 mg, about 100 mg to about 500 mg or about 10 to about 30 mg,of the active ingredient. In some embodiments, each dosage containsabout 10 mg of the active ingredient. In some embodiments, each dosagecontains about 50 mg of the active ingredient. In some embodiments, eachdosage contains about 25 mg of the active ingredient. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of one ormore compounds described herein. When referring to these pre-formulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid pre-formulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of thepresent disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds, or compositions as describedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufilation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of the compounds in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, compounds of the present disclosure canbe provided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

Compounds described herein can also be formulated in combination withone or more additional active ingredients, which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating FGFR3 protein in tissuesamples, including human, and for identifying FGFR3 ligands byinhibition binding of a labeled compound. Substitution of one or more ofthe atoms of the compounds of the present disclosure can also be usefulin generating differentiated ADME (Adsorption, Distribution, Metabolismand Excretion). Accordingly, the present invention includes FGFR bindingassays that contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsin Formula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind an FGFR3 protein by monitoring itsconcentration variation when contacting with the FGFR3, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a FGFR3 protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the FGFR3 protein directly correlates to its bindingaffinity. Conversely, in some other screening assays, the standardcompound is labeled and test compounds are unlabeled. Accordingly, theconcentration of the labeled standard compound is monitored in order toevaluate the competition between the standard compound and the testcompound, and the relative binding affinity of the test compound is thusascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, such as cancer and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof FGFR3 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass-directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.,“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [see“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature [See “PreparativeLCMS Purification: Improved Compound Specific Method Optimization”, K.Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].Typically, the flow rate used with 30×100 mm column was 60 mL/minute.

Intermediate 1.(9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-J][1,6]naphthyridin-3-yl)methanol

Step 1. 3-Bromo-5-chloro-1,6-naphthyridine

A flask containing a mixture of phosphoryl chloride (41.4 mL, 444 mmol)and 3-bromo-1,6-naphthyridin-5(6H)-one (5.0 g, 22.2 mmol) was stirred at100° C. for 3 h. The reaction mixture was cooled to room temperature andthe reaction mixture was concentrated in vacuo. The resulting residuewas cooled down to 0° C. and treated with saturated aqueous NaHCO₃ andthe mixture was extracted with EtOAc. The organic phase was washed withbrine, dried over MgSO₄, filtered and the solvent was evaporated invacuo. The obtained crude product was used in the next step withoutfurther purification. LCMS calculated for CsHsBrClN₂ (M+H)⁺:m/z=242.9/244.9; found: 243.0/244.9.

Step 2. 3-Bromo-1,6-naphthyridin-5-amine

A mixture of 3-bromo-5-chloro-1,6-naphthyridine (2.68 g, 11.0 mmol),1,4-dioxane (9 mL), and ammonium hydroxide solution (9 mL) in a sealedmicrowave vessel was irradiated at 150° C. for 3 h using a BiotageInitator+ Microwave Synthesizer. The reaction mixture was cooled to roomtemperature and the solvent was evaporated in vacuo. The obtained crudeproduct was used in the next step without further purification. LCMScalculated for C₈H₇BrN₃ (M+H)⁺: m/z=224.0/226.0; found: 224.2/226.2.

Step 3. 9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine

A microwave vessel containing a mixture of3-bromo-1,6-naphthyridin-5-amine (1.32 g, 5.89 mmol), sodium bicarbonate(742 mg, 8.84 mmol), 2-bromo-1-(2,6-dichlorophenyl)ethan-1-one (1.89 g,7.07 mmol) and tert-butanol (8 mL) was irradiated at 150° C. for 9 husing a Biotage Initator+ Microwave Synthesizer. After cooling to roomtemperature, the solid was filtered and washed with CH₂Cl₂, followed byconcentration of the filtrate in vacuo. The resulting residue waspurified by Biotage Isolera to give the desired product as an orangesolid. LCMS calculated for C₁₆H₉BrCl₂N₃(M+H)⁺: m/z=391.9/393.9/395.9;found 392.1/394.1/396.1.

Step 4.9-Bromo-2-(2,6-dichlorophenyl)-3-iodoimidazo[2,1-f][1,6]naphthyridine

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine (200 mg,0.509 mmol), NIS (114 mg, 0.509 mmol) in acetonitrile (2 mL) was stirredat 60° C. for 4 h. The solution was subsequently cooled to roomtemperature, concentrated in vacuo and purified by Biotage Isolera togive the desired product as a brown solid. LCMS calculated forC₁₆H₈BrCl₂IN₃ (M+H)⁺: m/z=517.8/519.8; found 517.9/519.7.

Step 5.9-Bromo-2-(2,6-dichlorophenyl)-3-vinylimidazo[2,1-f][1,6]naphthyridine

A mixture of9-bromo-2-(2,6-dichlorophenyl)-3-iodoimidazo[2,1-f][1,6]naphthyridine(150 mg, 0.289 mmol), potassium phosphate, tribasic (123 mg, 0.578mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 0.029 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (49 μL, 0.289 mmol) wassuspended in 1,4-dioxane (2 mL), and water (200 μL). The reactionmixture was purged with nitrogen for 30 sec and heated to 70° C. for 2h. Upon cooling to room temperature, the solution was diluted withCH₂Cl₂, filtered through Celite and the filtrate was concentrated invacuo. The resulting residue was purified by Biotage Isolera to give thedesired product as a brown solid. LCMS calculated for C₁₈H₁₁BrCl₂N3(M+H)⁺: m/z=418.0/419.9; found 418.1/420.1.

Step 6.(9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

To a vial was added9-bromo-2-(2,6-dichlorophenyl)-3-vinylimidazo[2,1-f][1,6]naphthyridine(80 mg, 0.191 mmol), THF (3 mL), water (1 mL) and osmium tetroxide (4wt. % in H₂O, 75 μL, 9.54 μmol), followed by sodium periodate (204 mg,0.954 mmol). The reaction mixture was stirred at room temperature for 3h, and upon completion the reaction was quenched with saturated aqueousNa₂S₂O₃ and extracted into EtOAc. The combined organic layers wereconcentrated in vacuo and the residue was dissolved in isopropanol (4mL), cooled to 0° C., and NaBH₄ (7.22 mg, 0.191 mmol) was added withstirring while allowing the reaction to slowly warm to room temperature.The reaction was then cooled to 0° C. and quenched by addition ofsaturated aqueous NH₄Cl. The volatiles were removed in vacuo and theresidue was extracted into 20:1 CH₂Cl₂/MeOH. The resulting organiclayers were combined and concentrated in vacuo. The obtained product wasused in the next step without further purification. LCMS calculated forC₁₇H₁₁BrCl₂N3O (M+H)⁺: m/z=421.9/423.9; found 421.9/424.0.

Example 1.(2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-J][1,6]naphthyridin-3-yl)methanol

Step 1.(2-(2,6-Dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

A flask containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 1.5 g, 3.55 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(1.26 g, 3.90 mmol), potassium phosphate, tribasic (2.26 g, 10.64 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (290 mg,0.355 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (28 mL) and water (7 mL). Thevial was sealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. The obtainedcrude product was then dissolved in CH₂Cl₂ (5 mL) and TFA (5 mL) andleft to stir at r.t. for 1 h. The reaction mixture was concentrated invacuo, then redissolved in MeOH (5 mL) and added to a stirring solutionof saturated aqueous NaHCO₃ (50 mL). The resulting precipitate wasfiltered and collected, followed by drying under vacuum. LCMS calculatedC₂₀H₁₄Cl₂N50 (M+H)⁺: m/z=410.1/412.1; found 410.0/412.1.

Step 2.(2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

To a vial containing a mixture of(2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(10 mg, 0.024 mmol) and cesium carbonate (24 mg, 0.073 mmol) as asolution in DMF (500 μL) was added 4-(bromomethyl)pyrimidinehydrobromide (9 mg, 0.037 mmol). The vial was sealed and heated to 50°C. for 2 h. After cooling to room temperature, the mixture was thendiluted with CH₃CN and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to provide the title compound as the TFA salt.LCMS calculated for C₂₅H₁₈Cl₂N₇O (M+H)⁺: m/z=502.1/504.1; found502.1/504.1. ¹H NMR (500 MHz, DMSO-d₆) δ 9.29 (d, J=2.3 Hz, 1H), 9.17(d, J=1.4 Hz, 1H), 8.97 (d, J=2.2 Hz, 1H), 8.79 (d, J=5.2 Hz, 1H), 8.76(s, 1H), 8.55 (d, J=7.5 Hz, 1H), 8.36 (s, 1H), 7.69-7.60 (m, 2H), 7.55(dd, J=8.8, 7.4 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.21 (dd, J=5.2, 1.4Hz, 1H), 5.56 (s, 2H), 4.68 (s, 2H).

Example 2.5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)nicotinonitrile

This compound was prepared according to the procedures described inExample 1, with 5-(bromomethyl)nicotinonitrile replacing4-(bromomethyl)pyrimidine hydrobromide in Step 2 to provide the titlecompound as the TFA salt. LCMS calculated for C₂₇H₁₈Cl₂N₇O (M+H)⁺:m/z=526.1/528.1; found: 526.0/528.0.

Example 3.5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)picolinonitrile

This compound was prepared according to the procedures described inExample 1, with 5-(bromomethyl)picolinonitrile replacing4-(bromomethyl)pyrimidine hydrobromide in Step 2 to provide the titlecompound as the TFA salt. LCMS calculated for C₂₇H₁₈Cl₂N₇O (M+H)⁺:m/z=526.1/528.1; found: 526.2/528.2.

Example 4.4-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)₁H-pyrazol-1-yl)methyl)picolinonitrile

This compound was prepared according to the procedures described inExample 1, with 4-(bromomethyl)picolinonitrile replacing4-(bromomethyl)pyrimidine hydrobromide in Step 2 to provide the titlecompound as the TFA salt. LCMS calculated for C₂₇H₁₈Cl₂N₇O (M+H)⁺:m/z=526.1/528.1; found: 526.1/528.1. ¹H NMR (500 MHz, DMSO-d₆) δ 9.28(d, J=2.2 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 8.77-8.72 (m, 2H), 8.56 (d,J=7.5 Hz, 1H), 8.36 (s, 1H), 7.95-7.91 (m, 1H), 7.66-7.62 (m, 2H),7.58-7.52 (m, 2H), 7.47 (d, J=7.5 Hz, 1H), 5.57 (s, 2H), 4.68 (s, 2H).

Example 5.(2-(2,6-Dichlorophenyl)-9-(1-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

This compound was prepared according to the procedures described inExample 1, with 4-(bromomethyl)-2-(trifluoromethyl)pyridine replacing4-(bromomethyl)pyrimidine hydrobromide in Step 2 to provide the titlecompound as the TFA salt. LCMS calculated for C₂₇H₁₈Cl₂F₃N₆O (M+H)⁺:m/z=569.1/571.1; found: 569.0/571.0.

Example 6.(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)(morpholino)methanone

A vial containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 15 mg, 0.035 mmol),(4-(morpholine-4-carbonyl)phenyl)boronic acid (17 mg, 0.071 mmol),potassium phosphate, tribasic (23 mg, 0.11 mmol), and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (4 mg, 5.3μmol) was evacuated and backfilled with nitrogen three times, followedby the addition of 1,4-dioxane (1 mL) and water (250 μL). The vial wassealed and heated to 80° C. for 30 minutes. After cooling to roomtemperature, the mixture was then diluted with CH₃CN and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₈H₂₃Cl₂N₄O₃ (M+H)⁺: m/z=533.1/535.1; found 533.1/535.1.

Example 7.((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)methanone

Step 1.4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzoicacid

A vial containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 100 mg, 0.236 mmol),(4-(tert-butoxycarbonyl)phenyl)boronic acid (79 mg, 0.355 mmol),potassium phosphate, tribasic (151 mg, 0.709 mmol), and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (29 mg,0.035 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (1 mL) and water (250 μL). Thevial was sealed and heated to 80° C. for 30 minutes. After cooling toroom temperature, the mixture was filtered through Celite and washedwith CH₂Cl₂, followed by concentration of the filtrate in vacuo. Theresulting residue was purified by Biotage Isolera to give the desiredproduct as a white solid. The purified product was then dissolved inCH₂Cl₂ (2 mL) and TFA (1 mL) and left to stir at r.t. for 1 h. Thereaction mixture was concentrated in vacuo, then dissolved in MeOH (1mL) and added to a stirring solution of saturated aqueous NaHCO₃ (10mL). The resulting precipitate was filtered and collected, followed bydrying under vacuum. LCMS calculated C₂₄H₁₆Cl₂N₃O₃ (M+H)⁺:m/z=464.1/466.1; found 464.0/466.0.

Step 2.((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)methanone

To a vial containing4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzoicacid (10 mg, 0.022 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptanehydrochloride (4.4 mg, 0.032 mmol), DMF (500 μL) and DIPEA (11 μL, 0.061mmol) was added HATU (12 mg, 0.032 mmol). The reaction mixture was leftto stir at r.t. for 1 h, upon which time water was added and theresulting solid was collected by filtration and washed with water. Thesolid was then dissolved with TFA and purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the title compound asthe TFA salt. LCMS calculated for C₂₉H₂₃Cl₂N₄O₃ (M+H)⁺: m/z=545.1/547.1;found 545.1/547.3.

Example 8.1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzyl)piperazin-1-yl)-2-hydroxyethan-1-one

Step 1.(2-(2,6-Dichlorophenyl)-9-(4-(piperazin-1-ylmethyl)phenyl)imidazo[2,1-f][1.6]naphthyridin-3-yl)methanol

A vial containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 100 mg, 0.236 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate(105 mg, 0.260 mmol), potassium phosphate, tribasic (151 mg, 0.709mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)(19 mg, 0.024 mmol) was evacuated and backfilled with nitrogen threetimes, followed by the addition of 1,4-dioxane (2 mL) and water (500μL). The vial was sealed and heated to 80° C. for 30 minutes. Aftercooling to room temperature, the mixture was filtered through Celite andwashed with CH₂Cl₂, followed by concentration of the filtrate in vacuo.The resulting residue was purified by Biotage Isolera to give thedesired product as a yellow solid. The purified product was thendissolved in CH₂Cl₂ (5 mL) and TFA (1 mL) and left to stir at r.t. for 1h. The reaction mixture was concentrated in vacuo, then dissolved inMeOH (1 mL) and added to a stirring solution of saturated aqueous NaHCO₃(10 mL). The resulting precipitate was filtered and collected, followedby drying under vacuum. LCMS calculated C₂₈H₂₆Cl₂N₅O (M+H)⁺:m/z=518.2/520.1; found 518.2/520.2.

Step 2.1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzyl)piperazin-1-yl)-2-hydroxyethan-1-one

To a vial containing(2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-ylmethyl)phenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(10 mg, 0.019 mmol), 2-hydroxyacetic acid (2 mg, 0.029 mmol), DMF (500μL) and DIPEA (7 μL, 0.039 mmol) was added HATU (11 mg, 0.029 mmol). Thereaction mixture was left to stir at r.t. for 1 h, upon which time waterwas added and the resulting solid was collected by filtration and washedwith water. The solid was then dissolved with TFA and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₃₀H₂₈Cl₂N₅O₃ (M+H)⁺: m/z=576.2/578.2; found 576.2/578.2.

Example 9.1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzyl)piperazin-1-yl)ethan-1-one

This compound was prepared according to the procedures described inExample 8, with acetic acid replacing 2-hydroxyacetic acid in Step 2 toprovide the title compound as the TFA salt. LCMS calculated forC₃₀H₂₈Cl₂N₅O₂ (M+H)⁺: m/z=560.2/562.2; found: 560.3/562.3.

Example 10.1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)piperazin-1-yl)-2-hydroxyethan-1-one

This compound was prepared according to the procedures described inExample 8, with tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylatereplacing tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylatein Step 1 to provide the title compound as the TFA salt. LCMS calculatedfor C₂₉H₂₆Cl₂N₅O₃ (M+H)⁺: m/z=562.1/564.1; found: 562.2/564.1.

Example 11.(2-(2-Chloro-6-methylphenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-J][1,6]naphthyridin-3-yl)methanol

Step 1.(2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

A vial containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 50 mg, 0.118 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine(105 mg, 0.260 mmol), potassium phosphate, tribasic (75 mg, 0.355 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (15 mg,0.018 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (1 mL) and water (250 μL). Thevial was sealed and heated to 80° C. for 30 minutes. After cooling toroom temperature, the mixture was filtered through Celite and washedwith CH₂Cl₂, followed by concentration of the filtrate in vacuo. Theresulting residue was purified by Biotage Isolera to give the desiredproduct as a yellow solid. LCMS calculated C₂₆H₂₅Cl₂N₆O (M+H)⁺:m/z=507.1/509.1; found 507.1/509.1.

Step 2.(2-(2-Chloro-6-methylphenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

A microwave vial containing a mixture of(2-(2,6-dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(84 mg, 0.166 mmol), Pd₂(dba)₃ (15 mg, 0.017 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (29 mg, 0.050 mmol), andpotassium carbonate (46 mg, 0.331 mmol) was evacuated and backfilledwith nitrogen three times, followed by the addition of 1,4-dioxane (12mL) and trimethylboroxine (26 μL, 0.182 mmol). The vial was irradiatedat 130° C. for 2 h using a Biotage Initator+ Microwave Synthesizer.After cooling to room temperature, the mixture was filtered throughCelite and washed with CH₂Cl₂, followed by concentration of the filtratein vacuo. The residue was then dissolved with CH₃CN and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₇H₂₈ClN₆O (M+H)⁺: m/z=487.2; found 487.2.

Example 12.5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)-N,N-dimethylpicolinamide

Step 1.5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)picolinicacid

To a vial containing a mixture of(2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(100 mg, 0.244 mmol) and cesium carbonate (159 mg, 0.487 mmol) as asolution in DMF (1 mL) was added methyl 5-(bromomethyl)picolinate (84mg, 0.366 mmol). The reaction mixture was left to stir at r.t. for 1 h,upon which time water was added and the resulting solid was collected byfiltration. The crude solid was dissolved in THF (2 mL) and 2M aq. LiOH(500 μL, 1.0 mmol) and left to stir at r.t. for 1 h, after which timethe pH was adjusted to ˜7 by addition of 1M aq. HCl. The resulting solidwas collected by filtration and washed with water, then left to dryunder vacuum. The obtained crude product was used in the next stepwithout further purification. LCMS calculated for C₂₇H₁₉Cl₂N₆O₃ (M+H)⁺:m/z=545.1/547.1; found: 545.1/547.1.

Step 2.5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)-N,N-dimethylpicolinamide

To a vial containing5-((4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)picolinicacid (10 mg, 0.018 mmol), dimethylamine (2M in EtOH, 14 μL, 0.028 mmol),DMF (0.5 mL) and DIPEA (6 μL, 0.037 mmol) was added HATU (10 mg, 0.028mmol). The reaction mixture was left to stir at r.t. for 1 h, upon whichtime water was added and the resulting solid was collected by filtrationand washed with water. The solid was then dissolved with TFA andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₉H₂₄Cl₂N₇O₂ (M+H)⁺: m/z=572.1/574.1; found 572.2/574.2.

Example 13.(3-(4-(2-(2,6-Dichlorophenyl)-3-methylimidazo[2,1-J][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methyl-1H-1,2,3-triazol-4-yl)methanone

Step 1.2-(2,6-Dichlorophenyl)-9-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine

A vial containing a mixture of9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine(Intermediate 1, Step 3, 1.0 g, 2.54 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(866 mg, 2.67 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (208 mg,0.254 mmol), and potassium phosphate, tribasic (1.62 g, 7.63 mmol) wasevacuated and backfilled with nitrogen three times, followed by theaddition of 1,4-dioxane (13.5 mL) and water (3.5 mL). The vial wassealed and heated to 80° C. for 30 min. After cooling to roomtemperature, the mixture was filtered through Celite and washed withCH₂Cl₂, followed by concentration of the filtrate in vacuo. The obtainedcrude residue was purified by Biotage Isolera to give the desiredproduct. LCMS calculated for C₂₅H₂₆Cl₂N₅OSi (M+H)⁺: m/z=510.1/512.1;found 510.1/512.1.

Step 2.3-Bromo-2-(2,6-dichlorophenyl)-9-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine

To a flask containing2-(2,6-dichlorophenyl)-9-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine(1.30 g, 2.54 mmol) as a solution in CH₂Cl₂ (25 mL) was added NBS (542mg, 3.05 mmol) and left to stir at r.t. for 10 min. The volatiles wereremoved under reduced pressure and the obtained crude product waspurified by Biotage Isolera to give the desired product. LCMS calculatedfor C₂₅H₂₅BrCl₂N₅OSi (M+H)⁺: m/z=588.0/590.0/592.0; found:588.2/590.2/592.2.

Step 3.2-(2,6-Dichlorophenyl)-3-methyl-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine

A vial containing a mixture of3-bromo-9-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine(1.97 g, 4.43 mmol), tetrakis(triphenylphosphine)palladium(0) (294 mg,0.254 mmol), and sodium carbonate (808 mg, 7.62 mmol) was evacuated andbackfilled with nitrogen three times, followed by the addition of1,4-dioxane (13 mL), water (3.5 mL), and trimethylboroxine (426 μL, 3.05mmol). The vial was sealed and heated to 100° C. overnight. Aftercooling to room temperature, the mixture was filtered through Celite andwashed with CH₂Cl₂, followed by concentration of the filtrate in vacuo.The obtained crude product was purified by Biotage Isolera to give thedesired product. The purified material was then dissolved in CH₂Cl₂ (10mL) and TFA (2 mL) and left to stir at r.t. for 2 h. The reactionmixture was concentrated in vacuo, then dissolved in MeOH (2 mL) andadded to a stirring solution of saturated aqueous NaHCO₃ (50 mL). Theresulting solid precipitate was filtered and collected, followed bydrying under vacuum overnight. LCMS calculated for C₂₀H₁₄Cl₂N₅ (M+H)⁺:m/z=394.1/396.1; found 394.0/396.0.

Step 4.9-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridine

To a vial containing a mixture of2-(2,6-dichlorophenyl)-3-methyl-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine(250 mg, 0.634 mmol), tert-butyl3-((methylsulfonyl)oxy)azetidine-1-carboxylate (319 mg, 1.27 mmol),cesium carbonate (620 mg, 1.90 mmol) was added acetonitrile (6.3 mL).The vial was sealed and heated to 80° C. for 16 h. After cooling to roomtemperature, the mixture was filtered through Celite and washed withacetonitrile, followed by concentration of the filtrate in vacuo. Theresulting residue was purified by Biotage Isolera to give the desiredproduct as a tan solid. The purified material was then dissolved inCH₂Cl₂ (3 mL) and TFA (1 mL) and left to stir at r.t. for 1 h. Thereaction mixture was concentrated in vacuo, then dissolved in MeOH (3mL) and added to a stirring solution of saturated aqueous NaHCO₃ (15mL). The resulting solid precipitate was filtered and collected,followed by drying under vacuum overnight. LCMS calculated forC₂₃H₁₉Cl₂N₆ (M+H)⁺: m/z=449.1/451.1; found: 449.1/451.1.

Step 5.(3-(4-(2-(2,6-Dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methyl-1H-1,2,3-triazol-4-yl)methanone

To a vial containing9-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridine(230 mg, 0.512 mmol) as a solution in DMF (2 mL) was added1-methyl-1H-1,2,3-triazole-4-carboxylic acid (98 mg, 0.768 mmol),diisopropylethylamine (358 μL, 2.05 mmol), and BOP (340 mg, 0.768 mmol).The reaction mixture was left to stir at r.t. for 1 h. Water was thenadded and the resulting solid was collected by filtration and washedwith water. The solid was then dissolved with TFA and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₇H₂₂Cl₂N₉O (M+H)⁺: m/z=558.1/560.1; found 558.1/560.1. ¹H NMR (500MHz, DMSO-d₆) δ 9.30 (d, J=2.2 Hz, 1H), 8.99 (d, J=2.2 Hz, 1H), 8.88 (d,J=0.7 Hz, 1H), 8.60 (s, 1H), 8.49 (d, J=7.5 Hz, 1H), 8.38 (d, J=0.7 Hz,1H), 7.69-7.64 (m, 2H), 7.57 (dd, J=8.7, 7.5 Hz, 1H), 7.46 (d, J=7.5 Hz,1H), 5.42 (tt, J=8.0, 5.2 Hz, 1H), 5.09 (ddd, J=10.4, 7.9, 1.2 Hz, 1H),4.87 (dd, J=10.4, 5.2 Hz, 1H), 4.59 (ddd, J=10.5, 8.1, 1.2 Hz, 1H), 4.38(dd, J=10.5, 5.2 Hz, 1H), 4.10 (s, 3H), 2.41 (s, 3H).

Example 14.(3-(4-(2-(2,6-Dichlorophenyl)-3-methylimidazo[2,1-J][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(2-methyl-2H-tetrazol-5-yl)methanone

This compound was prepared according to the procedures described inExample 13, with 2-methyl-2H-tetrazole-5-carboxylic acid replacing1-methyl-1H-1,2,3-triazole-4-carboxylic acid in Step 5 to provide thetitle compound as the TFA salt. LCMS calculated for C₂₆H₂₁Cl₂N₁₀O(M+H)⁺: m/z=559.1/561.1; found: 559.2/561.2. ¹H NMR (500 MHz, DMSO-d₆) δ9.28 (d, J=2.3 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 8.90 (s, 1H), 8.47 (d,J=7.5 Hz, 1H), 8.39 (s, 1H), 7.66 (d, J=8.1 Hz, 2H), 7.56 (dd, J=8.7,7.5 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 5.43 (tt, J=8.0, 5.2 Hz, 1H),5.10-5.03 (m, 1H), 4.86 (ddd, J=10.5, 5.1, 1.3 Hz, 1H), 4.67 (ddd,J=10.8, 8.1, 1.4 Hz, 1H), 4.47-4.41 (m, 4H), 2.40 (s, 3H).

Example 15.(2-(2,6-Dichlorophenyl)-9-(1-ethyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

A vial containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 15 mg, 0.035 mmol), (1-ethyl-1H-pyrazol-4-yl)boronicacid (5 mg, 0.035 mmol), potassium phosphate, tribasic (23 mg, 0.106mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)(2.6 mg, 3.55 μmol) was evacuated and backfilled with nitrogen threetimes, followed by the addition of 1,4-dioxane (1 mL) and water (100μL). The vial was sealed and heated to 80° C. for 30 minutes. Uponcompletion the reaction mixture was flushed through a SiliaPrep SPEthiol cartridge (SPE-R51030B-06P), diluted with acetonitrile/methanoland purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₂H₁₈Cl₂N₅O(M+H)⁺: m/z=438.1/440.1; found 438.1/440.1.

Example 16.2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile

This compound was prepared according to the procedures described inExample 15, with2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrilereplacing (1-ethyl-1H-pyrazol-4-yl)boronic acid to provide the titlecompound as the TFA salt. LCMS calculated for C₂₄H₁₉Cl₂N₆O (M+H)⁺:m/z=477.1/479.1; found: 477.1/479.1.

Example 17.2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile

This compound was prepared according to the procedures described inExample 15, with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrilereplacing (1-ethyl-1H-pyrazol-4-yl)boronic acid. LCMS calculated forC₂₃H₁₇Cl₂N₆O (M+H)⁺: m/z=463.1/465.1; found: 463.2/465.2. This racematewas separated into pure enantiomers by subjecting to chiral SFC(Phenomenex Lux Sum Cellulose-21.1×250 mm column, eluting with anisocratic solution of 35% MeOH in CO₂, at a flow rate of 65 mL/min,t_(R, peak 1)=2.8 min, t_(R, peak 2)=3.9 min). After the solvent wasevaporated in vacuo, each enantiomer was purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide each enantiomer of thetitle compound as the TFA salt. ¹H NMR (600 MHz, DMSO-d₆) δ 9.30 (d,J=2.3 Hz, 1H), 9.02 (dd, J=2.3, 0.7 Hz, 1H), 8.83 (d, J=0.8 Hz, 1H),8.57 (d, J=7.5 Hz, 1H), 8.44 (d, J=0.8 Hz, 1H), 7.72-7.60 (m, 2H), 7.56(dd, J=8.7, 7.6 Hz, 1H), 7.48 (dd, J=7.5, 0.7 Hz, 1H), 5.91 (q, J=7.1Hz, 1H), 4.69 (s, 2H), 1.88 (d, J=7.1 Hz, 3H).

Example 18.1-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propan-2-ol

This compound was prepared according to the procedures described inExample 15, with1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olreplacing (1-ethyl-1H-pyrazol-4-yl)boronic acid. LCMS calculated forC₂₃H₂₀Cl₂N₅O₂ (M+H)⁺: m/z=468.1/470.1; found: 468.1/470.1. This racematewas separated into pure enantiomers by subjecting to chiral SFC(Phenomenex Lux Sum Cellulose-21.1×250 mm column, eluting with anisocratic solution of 35% MeOH in CO₂, at a flow rate of 60 mL/mint_(R, peak 1)=6.6 min, t_(R, peak 2)=7.6 min). After the solvent wasevaporated in vacuo, each enantiomer was purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide each enantiomer of thetitle compound as the TFA salt.

Example 19.2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide

Step 1.2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)aceticacid

A vial containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 15 mg, 0.035 mmol), methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate(10 mg, 0.035 mmol), potassium phosphate, tribasic (23 mg, 0.106 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (2.6 mg,3.55 μmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (1 mL) and water (100 μL). Thevial was sealed and heated to 80° C. for 30 minutes. Upon completion thereaction mixture was flushed through a SiliaPrep SPE thiol cartridge(SPE-R51030B-06P). To the filtrate was added lithium hydroxide (15 mg,0.6 mmol) in 1 mL water, and the reaction mixture was left to stir for20 min. Upon completion, all volatiles were removed and the cruderesidue was used directly for the next step. LCMS calculated forC₂₂H₁₆Cl₂N₅O₃ (M+H)⁺: m/z=468.1/470.1; found 468.1/470.0.

Step 2.2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide

To a vial containing2-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)aceticacid (15 mg, 0.032 mmol) was added dimethylamine hydrochloride (3 mg,0.032 mmol), DMF (0.5 ml) and DIPEA (11 μL, 0.064 mmol). The solutionwas stirred for 1 min before adding HATU (18 mg, 0.048 mmol) and leavingto stir for 1 h. Upon completion, the reaction mixture was diluted withacetonitrile/methanol and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to provide the title compound as the TFA salt.LCMS calculated for C₂₄H₂₁Cl₂N₆O₂ (M+H)⁺: m/z=495.1/497.1; found495.1/497.0.

Example 20.1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one

Step 1.(2-(2,6-Dichlorophenyl)-9-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

A vial containing(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-][1,6]naphthyridin-3-yl)methanol(Intermediate 1, 50 mg, 0.118 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(45 mg, 0.118 mmol), potassium phosphate, tribasic (75 mg, 0.355 mmol),and (1,1′-bis(diphenylphosphino)ferrocene) dichloropalladium(II) (9 mg,0.012 mmol) was evacuated and backfilled with nitrogen three times,followed by the addition of 1,4-dioxane (1 mL) and water (100 μL). Thevial was sealed and heated to 80° C. for 30 minutes. Upon completion thereaction was diluted with CH₂Cl₂, and flushed through celite. Thefiltrate was concentrated in vacuo, and taken up in 1 mL CH₂Cl₂ and 0.5mL TFA. Upon reaction completion, the volatiles were removed and theresidue was suspended in MeOH (1 mL) and poured into sat aq. NaHCO₃. Theresulting precipitate was filtered, dried under vacuum and used directlyfor the next step. LCMS calculated for C₂₅H₂₃Cl₂N₆O(M+H)⁺:m/z=493.1/495.1; found 493.1/495.0.

Step 2.1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one

To a vial containing(2-(2,6-dichlorophenyl)-9-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(10 mg, 0.020 mmol) was added acetic acid (1.2 μL, 0.020 mmol), DMF (0.5mL) and DIPEA (7 μL, 0.04 mmol). The solution was stirred for 1 minbefore adding HATU (12 mg, 0.03 mmol) and leaving to stir for 1 h. Uponcompletion the reaction mixture was diluted with acetonitrile/methanoland purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₇H₂₅Cl₂N₆O₂(M+H)⁺: m/z=535.1/537.1; found 535.1/537.1.

Example 21.1-(4-(4-(2-(2-Chloro-6-methylphenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethan-1-one

Step 1.1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethan-1-one

This compound was prepared according to the procedures described inExample 20, with 2-methoxyacetic acid replacing acetic acid in Step 2.LCMS calculated for C₂₈H₂₇Cl₂N₆O₃ (M+H)⁺: m/z=565.2/567.2; found:565.2/567.2.

Step 2.1-(4-(4-(2-(2-Chloro-6-methylphenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethan-1-one

A microwave vial containing a mixture of1-(4-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethan-1-one(25 mg, 0.044 mmol), Pd₂(dba)₃ (2 mg, 2.2 μmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (4 mg, 6.63 μmol), andpotassium carbonate (12 mg, 0.088 mmol) was evacuated and backfilledwith nitrogen three times, followed by the addition of 1,4-dioxane (2mL) and trimethylboroxine (7 μL, 0.05 mmol). The vial was irradiated at130° C. for 2 h using a Biotage Initator+ Microwave Synthesizer. Aftercooling to room temperature, the mixture was filtered through celite andwashed with CH₂Cl₂, followed by concentration of the filtrate in vacuo.The residue was then dissolved with CH₃CN and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to provide the titlecompound as the TFA salt. LCMS calculated for C₂₉H₃₀ClN₆O₃(M+H)⁺:m/z=545.2; found 545.3.

Example 22.1-(4-(2-(2-Chloro-6-methylphenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

This compound was prepared according to the procedures described inExample 11, with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olreplacing1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidinein Step 1 to provide the title compound as the TFA salt. LCMS calculatedfor C₂₅H₂₅ClN₅O₂ (M+H)⁺: m/z=462.2; found: 462.2. ¹H NMR (600 MHz,DMSO-d₆) δ 9.30 (d, J=2.3 Hz, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.57 (d,J=7.4 Hz, 1H), 8.47 (s, 1H), 8.21 (s, 1H), 7.51 (d, J=7.3 Hz, 1H),7.48-7.42 (m, 2H), 7.40-7.36 (m, 1H), 4.75 (d, J=13.6 Hz, 1H), 4.57 (d,J=13.6 Hz, 1H), 4.09 (s, 2H), 2.18 (s, 3H), 1.12 (s, 6H).

Example 23.3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)butanenitrile

To a vial containing a mixture of(2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(Example 1, Step 1, 15 mg, 0.037 mmol) and cesium carbonate (15 mg,0.044 mmol) as a solution in DMF (500 μL) was added 3-bromobutanenitrile(6 mg, 0.037 mmol). The vial was sealed and heated to 80° C. for 16 h.After cooling to room temperature, the mixture was then diluted withCH₃CN and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₄H₁₉Cl₂N₆O (M+H)⁺: m/z=477.1/479.1; found477.2/479.2. This racemate was separated into pure enantiomers bysubjecting to chiral SFC (Phenomenex Lux Sum Cellulose-21.1×250 mmcolumn, eluting with an isocratic solution of 30% MeOH in CO₂, at a flowrate of 60 mL/min t_(R, peak 1)=10.4 min, t_(R, peak 2)=11.75 min).After the solvent was evaporated in vacuo, both enantiomers werepurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide each enantiomer of the title compound as the TFA salt. ¹H NMR(600 MHz, DMSO-d₆) δ 9.30 (d, J=2.2 Hz, 1H), 8.99 (d, J=2.3 Hz, 1H),8.77 (s, 1H), 8.56 (d, J=7.4 Hz, 1H), 8.34 (s, 1H), 7.65 (d, J=8.1 Hz,2H), 7.56 (dd, J=8.7, 7.6 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 4.80 (h,J=6.7 Hz, 1H), 4.69 (s, 2H), 3.18-3.15 (m, 2H), 1.59 (d, J=6.8 Hz, 3H).

Example 24.(R)-2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propan-1-ol

This compound was prepared according to the procedures described inExample 23, with (S)-2-chloropropan-1-ol replacing 3-bromobutanenitrileto provide the title compound as the TFA salt. LCMS calculated forC₂₃H₂₀Cl₂N₅O₃ (M+H)⁺: m/z=468.1/470.1; found: 468.1/470.1.

Example 25.(2-(2,6-Dichlorophenyl)-9-(1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-J][1,6]naphthyridin-3-yl)methanol

This compound was prepared according to the procedures described inExample 23, with 4-(bromomethyl)-4-fluorotetrahydro-2H-pyran replacing3-bromobutanenitrile to provide the title compound as the TFA salt. LCMScalculated for C₂₆H₂₃Cl₂FN₅O₂ (M+H)⁺: m/z=526.1/528.1; found:526.1/528.1.

Example 26.3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran1,1-dioxide

This compound was prepared according to the procedures described inExample 23, with 4-iodotetrahydro-2H-thiopyran 1,1-dioxide replacing3-bromobutanenitrile. [note: the 4-substituted thiopyrandioxide productwas not observed] LCMS calculated for C₂₅H₂₂Cl₂-N₅O₃S (M+H)⁺:m/z=542.1/544.1; found: 542.1/544.1. This racemate was separated intopure enantiomers by subjecting to chiral HPLC (Phenomenex Lux SumCellulose-21.2×250 mm column, eluting with an isocratic solution of 85%EtOH in hexanes, at a flow rate of 20 mL/min t_(R, peak 1)=11.2 min,t_(R, peak 2)=15.6 min). After the solvent was evaporated in vacuo, bothenantiomers were purified by prep-LCMS (XBridge C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide each enantiomer of the title compound as the TFA salt¹H NMR (600 MHz, DMSO-d₆) δ 9.25 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.3 Hz,1H), 8.74 (s, 1H), 8.54 (d, J=7.5 Hz, 1H), 8.32 (s, 1H), 7.65 (d, J=8.1Hz, 2H), 7.55 (dd, J=8.7, 7.6 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 4.75-4.64(m, 3H), 3.70 (dd, J=13.3, 11.9 Hz, 1H), 3.63 (dtd, J=13.5, 3.8, 1.5 Hz,1H), 3.21 (dtd, J=28.1, 14.1, 3.8 Hz, 2H), 2.20 (tdd, J=14.4, 6.8, 3.3Hz, 2H), 2.12-2.03 (m, 1H), 1.92 (tdd, J=12.8, 10.8, 3.6 Hz, 1H).

Example 27.1-(3-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)azetidin-1-yl)-2-methoxyethan-1-one

Step 1.(9-(1-(Azetidin-3-ylmethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol

This compound was prepared according to the procedures described inExample 20, with tert-butyl3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylatereplacing tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatein Step 1. LCMS calculated for C₂₄H₂₁Cl₂N₆O (M+H)⁺: m/z=479.1/481.1;found: 479.3/481.2.

Step 2.1-(3-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)azetidin-1-yl)-2-methoxyethan-1-one

To a vial containing(9-(1-(azetidin-3-ylmethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol(10 mg, 0.021 mmol) was added 2-methoxyacetic acid (2 μL, 0.020 mmol),DMF (500 μl) and DIPEA (7 μL, 0.04 mmol). The solution was stirred for 1min before adding HATU (12 mg, 0.03 mmol) and leaving to stir for 1 h.Upon completion the reaction mixture was diluted withacetonitrile/methanol and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to provide the title compound as the TFA salt.LCMS calculated for C₂₇H₂₅Cl₂N₆O₃ (M+H)⁺: m/z=551.1/553.1; found551.2/553.2.

Example 28.2-(2,6-Dichlorophenyl)-3-(difluoromethyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine

Step 1.9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carbaldehyde

To a vial was added9-bromo-2-(2,6-dichlorophenyl)-3-vinylimidazo[2,1-f][1,6]naphthyridine(240 mg, 0.573 mmol), THF (4.5 mL), water (1.1 mL) and osmium tetroxide(4 wt. % in H₂O, 91 μL, 14 μmol), followed by sodium periodate (612 mg,2.86 mmol). The reaction mixture was stirred at 30° C. for 2 h, and uponcompletion the reaction was quenched with saturated aqueous Na₂S₂O₃ andextracted into EtOAc. The combined organic layers were concentrated invacuo. The resulting residue was purified by Biotage Isolera to give thedesired product as a yellow oil. LCMS calculated for C₁₇H₉BrCl₂N₃O(M+H)⁺: m/z=419.9/421.9; found 419.9/421.9.

Step 2.9-Bromo-2-(2,6-dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridine

To a vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carbaldehyde(97 mg, 0.230 mmol) as a solution in CH₂Cl₂ (1.0 mL) at 0° C. was addeddiethylaminosulfur trifluoride (152 μL, 1.152 mmol) in a dropwisefashion. The reaction mixture was stirred at 40° C. for 16 h, and uponcompletion the reaction was carefully quenched with saturated aqueousNaHCO₃ and extracted into EtOAc. The combined organic layers wereconcentrated in vacuo. The resulting residue was purified by BiotageIsolera to give the desired product as a yellow oil. LCMS calculated forC₁₇H₉BrCl₂F₂N₃(M+H)⁺: m/z=441.9/443.9; found 441.9/443.9.

Step 3.2-(2,6-Dichlorophenyl)-3-(difluoromethyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine

A vial containing9-bromo-2-(2,6-dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridine(90 mg, 0.203 mmol),1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(73 mg, 0.244 mmol), potassium phosphate, tribasic (86 mg, 0.406 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)dichloromethane adduct (17 mg, 0.020 mmol) was evacuated and backfilledwith nitrogen three times, followed by the addition of 1,4-dioxane (1.9mL) and water (190 μL). The vial was sealed and heated to 80° C. for 1h. After cooling to room temperature, the mixture was filtered through aSiliaPrep SPE thiol cartridge (SPE-R51030B-06P) and washed withacetonitrile. The mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₃H₁₈Cl₂F₂N₅O₂S (M+H)⁺: m/z=536.1/538.0; found 536.0/538.0. ¹H NMR (500MHz, DMSO-dd S 9.35 (d, J=2.3 Hz, 1H), 9.02 (d, J=2.2 Hz, 1H), 8.73 (s,1H), 8.59 (d, J=7.5 Hz, 1H), 8.36 (s, 1H), 7.70-7.64 (m, 2H), 7.63-7.55(m, 2H), 7.54-7.17 (m, 1H), 4.61 (t, J=6.9 Hz, 2H), 3.78 (t, J=6.8 Hz,2H), 2.92 (s, 3H).

Example 29.2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)acetonitrile

This compound was prepared according to the procedures described inExample 28, with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrilereplacing1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein Step 3 to provide the title compound as the TFA salt. LCMS calculatedfor C₂₂H₁₃Cl₂F₂N₆ (M+H)⁺: m/z=469.1/471.1; found 469.0/471.0.

Example 30.2-(2,6-Dichlorophenyl)-3-(difluoromethyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-J][1,6]naphthyridine

This compound was prepared according to the procedures described inExample 28, with1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein Step 3 to provide the title compound as the TFA salt. LCMS calculatedfor C₂₅H₂₀Cl₂F₂N₅O (M+H)⁺: m/z=514.1/516.1; found 514.1/516.0.

Example 31.2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)ethan-1-ol

This compound was prepared according to the procedures described inExample 28, with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olreplacing1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein Step 3 to provide the title compound as the TFA salt. LCMS calculatedfor C₂₂H₁₆Cl₂F₂N₅O (M+H)⁺: m/z=474.1/476.1; found 474.0/476.0.

Example 32.2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile

This compound was prepared according to the procedures described inExample 28, with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrilereplacing1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein Step 3 to provide the title compound as the TFA salt. LCMS calculatedfor C₂₃H₁₅Cl₂F₂N₆ (M+H)⁺: m/z=483.1/485.1; found 483.0/485.0.

Example 33.2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

This compound was prepared according to the procedures described inExample 28, with2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanamidereplacing1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein Step 3 to provide the title compound as the TFA salt. LCMS calculatedfor C₂₄H₁₉Cl₂F₂N₆O (M+H)⁺: m/z=515.1/517.1; found 515.1/517.0.

Example 34.2-(2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)ethan-1-ol

Step 1.2-(9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)ethan-1-ol

To a vial containing9-bromo-2-(2,6-dichlorophenyl)-3-vinylimidazo[2,1-f][1,6]naphthyridine(40 mg, 0.095 mmol) as a solution in THF (320 μL) was added9-borabicyclo[3.3.1]nonane (0.5 M in THF, 380 μL, 0.190 mmol). Thereaction mixture was stirred at 50° C. for 16 h. Upon consumption of thestarting material, 2M aqueous sodium hydroxide (500 μL) and hydrogenperoxide (30% wt % in H₂O, 200 μL) was added to the vial. The reactionmixture was stirred at 50° C. for another 3 h. After cooling to roomtemperature, the solution was quenched with saturated aqueous NaHCO₃ andextracted into EtOAc. The combined organic layers were concentrated invacuo. The resulting residue was purified by Biotage Isolera to give thedesired product as a yellow oil. LCMS calculated for C₁₈H₁₃BrCl₂N₃O(M+H)⁺: m/z=436.0/438.0; found 436.0/438.0.

Step 2.2-(2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)ethan-1-ol

A vial containing2-(9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)ethan-1-ol(3 mg, 6.9 μmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine(6 mg, 21 μmol), potassium phosphate, tribasic (4 mg, 21 μmol), and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)dichloromethane adduct (1 mg, 1.4 μmol) was evacuated and backfilledwith nitrogen three times, followed by the addition of 1,4-dioxane (300μL) and water (30 μL). The vial was sealed and heated to 80° C. for 1 h.After cooling to room temperature, the mixture was filtered through aSiliaPrep SPE thiol cartridge (SPE-R51030B-06P) and washed withacetonitrile. The mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₇H₂₇Cl₂N₆O (M+H)⁺: m/z=521.2/523.2; found 521.1/523.1.

Example 35.2-(2,6-Dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-amine

Step 1.9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-amine

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine (140 mg,0.356 mmol), tert-butyl nitrite (184 mg, 1.781 mmol) in acetonitrile(1.4 mL) was stirred at 50° C. for 16 h. The solution was subsequentlycooled to room temperature, concentrated in vacuo and the residue wasdissolved in MeOH (2 mL), and Pd/C (10 wt %, 28 mg, 0.026 mmol) wasadded. The vial was purged with hydrogen for 5 min and then stirred for1 h under an atmosphere of hydrogen. The reaction mixture was thenfiltered and washed with CH₂Cl₂, followed by concentration of thefiltrate in vacuo. The resulting residue was purified by Biotage Isolerato give the desired product as an orange solid. LCMS calculated forC₁₆H₁₀BrCl₂N₄(M+H)⁺: m/z=406.9/408.9; found 407.0/409.0.

Step 2.2-(2,6-Dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-amine

A vial containing9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-amine(12 mg, 0.029 mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(16 mg, 0.059 mmol), potassium phosphate, tribasic (13 mg, 0.059 mmol),and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)dichloromethane adduct (2.4 mg, 2.9 μmol) was evacuated and backfilledwith nitrogen three times, followed by the addition of 1,4-dioxane (270μL) and water (27 μL). The vial was sealed and heated to 80° C. for 1 h.After cooling to room temperature, the mixture was filtered through aSiliaPrep SPE thiol cartridge (SPE-R51030B-06P) and washed withacetonitrile. The mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the title compound as the TFA salt. LCMS calculated forC₂₄H₂₁Cl₂N₆O (M+H)⁺: m/z=479.1/481.1; found 479.1/481.1.

Example A: FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was determined in anenzyme discontinuous assay that measures peptide phosphorylation usingFRET measurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.2 μL was transferred to the wells of a384-well plate. A 5 μL/well volume of enzyme isoforms of FGFR (-1, -2,-3 wild-type and mutant isoforms, -4) including phosphorylated andun-phosphorylated proteins diluted in assay buffer (50 mM HEPES, 10 mMMgCl₂, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT, pH 7.5) was added to theplate and pre-incubated with inhibitor for 5 to 15 minutes at ambienttemperature. Appropriate controls (enzyme blank and enzyme with noinhibitor) were included on the plate. The reaction was initiated by theaddition of a 5 μL/well volume containing both biotinylatedEQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP in assaybuffer. The 10 μL/well reaction concentration of the peptide substratewas 500 nM whereas the ATP concentration was maintained near or belowthe ATP Km. The ATP Km values were pre-determined in a separate seriesof experiments. The reaction plate was incubated at 25° C. for 1 hr andthe reactions were ended with the addition of 5 μL/well of quenchsolution (50 mM Tris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 45 mM EDTA,600 nM staurosporin, with Perkin Elmer Lance Reagents at 3.75 nMEu-antibody PY20 and 180 nM APC-Streptavidin). The plate was allowed toequilibrate for ˜10 minutes at ambient temperature before scanning on aPheraStar plate reader (BMG Labtech) instrument.

Either GraphPad prism or XLfit was used to analyze the data. The IC₅₀values were derived by fitting the data to a four parameter logisticequation producing a sigmoidal dose-response curve with a variable Hillcoefficient. Prism equation: Y=Bottom+(Top−Bottom)/(1+10{circumflex over( )}((Log IC₅₀−X)*Hill slope)); XLfit equation:Y=(A+((B−A)/(1+((X/C){circumflex over ( )}D)))) where X is the logarithmof inhibitor concentration and Y is the response. Compounds having anIC₅₀ of 1 μM or less are considered active.

Table 1 provides IC₅₀ data for compounds of the disclosure assayed inthe FGFR Enzymatic Assay after dilution in assay buffer, added to theplate and pre-incubated for 4 hours. The symbol: “+” indicates an IC₅₀less than 1.0 nM; “++” indicates an IC₅₀ greater than or equal to 1.0 nMbut less than 5.0 nM.

The data in Table 1 was measured in wild-type un-phosphorylated FGFR3protein.

TABLE 1 Example No. FGFR3 IC₅₀ (nM) 1 ++ 2 + 3 + 4 + 5 ++ 6 ++ 7 ++ 8 ++9 ++ 10 ++ 11 ++ 12 + 13 ++ 14 ++ 15 ++ 16 ++ 17 peak 1 + 17 peak 2 + 18peak 1 ++ 18 peak 2 ++ 19 ++ 20 + 21 ++ 22 ++ 23 peak 1 + 23 peak 2 + 24++ 25 + 26 peak 1 ++ 26 peak 2 + 27 ++ 28 + 29 + 30 + 31 + 32 + 33 + 34++ 35 ++

Example H: Luminescent Viability Assay

RT112 cells (cell lines and genetic profiles further detailed in Table2) were purchased from ATCC (Manassas, Va.) and maintained in RPMI, 10%FBS (Gibco/Life Technologies). To measure the effect of test compoundson the viability of cells, the cells were plated with RPMI 10% FBS(5×103 cells/well/in 50 μL) into black 96-well Greiner polystyrene inthe presence or absence of 50 μL of a concentration range of testcompounds. After 3 days, 100 μL of CellTiter-Glo Reagent (Promega) wasadded. Luminescence was read with a TopCount (PerkinElmer). IC₅₀determination was performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

TABLE 2 Cell line Histology FGFR2/3 alteration RT-112/84 BladderFGFR3-TACC3 RT112 Bladder FGFR3-TACC3 RT-112 V555M* Bladder FGFR3-TACC3V555M UM-UC-14 Bladder FGFR3 S249C RT-4 Bladder FGFR3-TACC3 SW-780Bladder FGFR3-BAIAP2L1 KMS-11 Multiple IgH-FGFR3 Myeloma translocation +FGFR3 Y373C OPM-2 Multiple IgH-FGFR3 Myeloma translocation + FGFR3 K650EKATO-III Stomach FGFR2 amplification SNU-16 Stomach FGFR2 amplificationAN3CA Endometrial FGFR2 N310R/N549K Ba/F3-FGFR2-BICC1 EngineeredFGFR2-BICC1** system Ba/F3-TEL-FGFR3 Engineered TEL-FGFR3 systemBa/F3-TEL-FGFR3 V555M Engineered TEL-FGFR3 V555M system Ba/F3-TEL-FGFR3V555L Engineered TEL-FGFR3 V555L system *RT112 V555M: V555M mutation wasengineered using CRISPR-mediated genome editing. **FGFR2-BICC1 fusionrepresents the most prevalent FGFR2 alteration in cholangiocarcinoma.

Table 3 provides IC₅₀ data for compounds of the disclosure assayed inthe luminescent viability assay for the RT-112/84 cell line. The symbol:“+” indicates an IC₅₀ less than 10 nM; “++” indicates an IC₅₀ greaterthan or equal to 10 nM but less than 50 nM.

TABLE 3 Example No. RT-112/84 IC₅₀ (nm) 1 ++ 2 ++ 3 + 4 + 5 + 6 ++ 7 ++8 ++ 9 ++ 10 ++ 11 ++ 12 + 13 ++ 14 ++ 15 + 16 ++ 17 peak 1 + 17 peak2 + 18 peak 1 ++ 18 peak 2 ++ 19 ++ 20 + 21 + 22 ++ 23 peak 1 ++ 23 peak2 ++ 24 ++ 25 + 26 peak 1 ++ 26 peak 2 + 27 ++ 28 + 29 + 30 + 31 + 32 +33 + 34 ++ 35 ++

Example C: pFGFR2 and pFGFR1,3 Functional Cell HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 2 (FGFR2),KATOIII cells (Human Gastric Carcinoma) are purchased from ATCC andmaintained in Iscove's with 20% FBS (Gibco/Life Technologies). For thepFGFR2 assay, KATOIII cells are plated overnight in 5% FBS and Iscove'smedium at 5×10⁴ cells/well into Corning 96-well flat-bottom tissueculture treated plates. The next morning, 50 μl of fresh media with 0.5%FBS is incubated in the presence or absence of a concentration range oftest compounds also at 50 ul, for 1 hour at 37° C., 5% CO2. Cell arewashed with PBS, lysed with Cell Signaling Lysis Buffer with standardProtease inhibitors for 45 min at room temperature. 4 μl total of CisBio Anti Phospho-YAP d2 and Cis Bio Anti Phospho-YAP Cryptate togetherare added to the lysate and mixed well (following directions of thekit). 16 μl is then transferred to 384 well Greiner white plates andstored at 4° C. overnight in the dark. Plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3),in house stable cell lines BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 ug/ml puromycin (Gibco/LifeTechnologies). For the assay, 12 nl of BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3cells in serum free and puromycin free RPMI media at 1×10⁶ cell/ml areadded to 384 Greiner white plate already containing 20 nl dots ofcompounds at a concentration range. The plates are gently shaken (100rpm) for 2 minutes at room temperature to mix well and incubate for 2hours in a single layer at 37° C., 5% CO2. 4 μl/well of 1/25 dilution oflysis buffer #3 (Cis Bio) is added with standard Protease inhibitors andshaken at 200 rpm at room temperature for 20 minutes. 4 μl total of theCis Bio Tb-pFGFR Ab (10 ng) and d2-FGFR3 (1 ng) together are added tothe lysate and mixed well. The plates are sealed and incubated at roomtemperature overnight in the dark. The plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Example D: pFGFR3 Functional Whole Blood HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3) ina whole blood assay, in house stable cell lines BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 μg/ml puromycin (Gibco/LifeTechnologies). For the assay, 100 ul BAF3-TEL-FGFR3 cells in 10% FBS andpuromycin free RPMI media at 5×10⁴ cell/well are added to fibronectincoated 96 well tissue culture plate (5 ug/ml) overnight at 37° C., 5%CO2. The next day, serum is separated from the top of the blood by a lowspeed spin, 1200, RPM, and heat inactivated by incubating at 56° C. for15 minutes. 30 μl of the cooled serum is added to a 96 well plate predotted with 70 nM dots of compounds at a concentration range. Cellplates are washed gently with media, all the blood/compound mixture isadded to the plates, and the plates are incubated for 2 hours at 37° C.,5% CO2. Blood from the plate is gently washed twice by adding media tothe side of the wells and then dumping media from the plate, andallowing the plate to briefly sit on a paper towel to drain. 70 μl/wellof 1× of lysis buffer #1 (Cis Bio) are added with standard Proteaseinhibitors, and are shaken at 400 rpm at room temperature for 30minutes. Following lysis, the plate is spun down for 5 minutes and 16 uLof lysate is transferred into a 384-well small volume plate. 4 μl totalof the Cis Bio Tb-pFGFR Ab (10 ng) and d2-FGFR3 (1 ng) together areadded to the lysate and mixed well. The plates are sealed and incubatedat room temperature overnight in the dark. Plates are read on thePherastar plate reader at 665 nm and 620 nm wavelengths. IC₅₀determination is performed by fitting the curve of inhibitor percentinhibition versus the log of the inhibitor concentration using theGraphPad Prism 5.0 software.

Example E: KATOIII Whole Blood pFGFR2α ELISA Assay

To measure tyrosine-phosphorylated Fibroblast Growth Factor Receptor 2alpha (FGFR2α) in KATO III spiked whole blood assay, KATO III cells arepurchased from ATCC and maintained in Iscove's medium with 20% FBS(Gibco/Life Technologies). To measure the inhibition of FGFR2α activityof test compounds, the cells are resuspended with Iscove's, 0.2% FBS at5×10⁶ cells/ml. 50 μL of the cells are then spiked into a 96-deep well 2ml polypropylene assay block (Costar) in the presence or absence of aconcentration range of test compounds and 300 ul human heparinized wholeblood (Biological Specialty Corp, Colmar Pa.). After 4 hours incubationin 37° C., the red cells are lysed using Qiagen EL buffer and the celllysates are resuspended in lysis buffer (Cell Signaling) containingstandard protease inhibitor cocktail (Calbiochem/EMD) and PMSF (Sigma)for 30 minutes ice. The lysates are transferred to a standard V bottompropylene tissue culture plate and frozen overnight at −80° C. Samplesare tested an in an R & D Systems DuoSet IC Human Phospho-FGF R2a, ELISAand the plate is measured using a SpectraMax M5 microplate set to 450 nmwith a wavelength correction of 540. IC₅₀ determination is performed byfitting the curve of inhibitor percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 5.0 software.

Example F: Inhibition of FGFR Pathway

The cellular potency of compounds is determined by measuringphosphorylation of FGFR or FGFR downstream effectors Fibroblast growthfactor receptor substrate 2 (FRS2) and extracellular-signal-regulatedkinase (ERK) in cell lines with FGFR2/3 alterations.

To measure phosphorylated Fibroblast growth factor receptor, Fibroblastgrowth factor receptor substrate 2 (FRS2) andextracellular-signal-regulated kinase (ERK) cells (details regarding thecell lines and types of data produced are further detailed in Table 4)are seeded in 6 well plates overnight in 10% FBS and RPMI medium at5-7.5×10⁵ cells/well into Corning 6-well tissue culture treated plates.The next morning, 2 ml of fresh media with 10% FBS is incubated in thepresence or absence of a concentration range of test compounds for 4hours at 37° C., 5% CO2. Cells are washed with PBS and lysed with CellSignaling Lysis Buffer with standard Protease inhibitors. 20-40 μg oftotal protein lysates are applied to western blot analysis usingantibodies: phosphor-FRS2 Tyr436 (AF5126) from R&D Systems (Minneapolis,Minn.)), phosphor-FGFR-Tyr653/654 (#2476S), phospho-ERK1/2-Thr202/Tyr204(#9101L) and total-ERK1/2 (#9102L) from Cell Signaling Technologies(Danvers, Mass.)).

TABLE 4 FGFR2/3 Cell line Histology alteration Readout RT-112/84 BladderFGFR3-TACC3 pFRS2, pERK RT112 V555M Bladder FGFR3-TACC3 pFRS2, pERKV555M UM-UC-14 Bladder FGFR3 S249C pFRS2, pERK KMS-11 Multiple IgH-FGFR3pFRS2, pERK Myeloma translocation + FGFR3 Y373C KATO-III Stomach FGFR2pFGFR, pERK amplification SNU-16 Stomach FGFR2 pFGFR, pERK amplification

Example G: Activity on In Vivo Tumor Models Harboring FGFR2/3 Alteration

In vivo activity of compounds is determined by measuring tumor growthwhen treated with various doses of compounds in FGFR2/3 altered models.

RT112/84 tumor cells (85061106, ECACC, UK) are maintained as recommendedby the source (tumor models are further detailed in Table 5). On Day 0of the experiments, 2.0×10⁶ RT112/84 cells are inoculated with a 1:1 PBSto Matrigel (354263, Coning) subcutaneously into the right hind flank offemale NSG mice (Jackson). Treatment with compounds at 0 (Vehicle). 100mg/kg, 30 mg/kg or 10 mg/kg PO QD is initiated on Day 7 after tumorinoculation, when tumors averaged approximately 200 mm, and is continueduntil the end of study. Mice are monitored for tumor growth and overttolerability over the course of the experiment. Tumor volume iscalculated using the formula (L×W²)/2, where L and W refer to the lengthand width dimensions, respectively. Tumor growth inhibition (TGI) iscalculated using the formula (1−(V_(T)/V_(C)))*100 where V_(T) is thetumor volume of the treatment group on the last day of treatment, andV_(C) is the tumor volume of the control group on the last day oftreatment. One-way ANOVA is used to determine statistical differencesbetween treatment groups at the end of the study.

TABLE 5 Tumor model Histology FGFR2/3 alteration RT-112/84 BladderFGFR3-TACC3 RT112 V555M Bladder FGFR3-TACC3 V555M UM-UC-14 Bladder FGFR3S249C KMS-11 Multiple Myeloma IgH-FGFR3 translocation + FGFR3 Y373CKATO-III Stomach FGFR2 amplification SNU-16 Stomach FGFR2 amplificationBa/F3-TEL- Engineered system TEL-FGFR3 V555M FGFR3 V555M

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound having Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R^(X) isselected from methyl and Cl; Cy¹ is selected from

R¹ is selected from CH₂OH, CH₂CH₂OH, CHF₂, NH₂, and CH₃; R² is selectedfrom ethyl, —(C₁₋₄ alkyl)-OH, —(C₁₋₃ alkyl)-CN, (C₁₋₃ alkyl)-C(O)NH₂,—(C₁₋₄ alkyl)-C(O)N(CH₃)₂, CH₂CH₂S(O)₂CH₃, and the following groups:

R^(2A) is selected from CH₃, C(O)CH₃, C(O)CH₂OCH₃, and C(O)CH₂OH; R^(2B)is selected from H, CN, CF₃, and C(O)N(CH₃)₂; and R^(2C) is selectedfrom H and F; provided that the compound is not:2-(2,6-Dichlorophenyl)-3-methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine,3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile,1-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)acetonitrile,(2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol,2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol,(2-(2,6-Dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol,or2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)ethan-1-ol.2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(X) is methyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(X) is Cl.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy¹ is Cy¹-1:


5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Cy¹ is Cy¹-2:


6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from CH₂CH₂OH, CHF₂, and NH₂.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from CH₂OH and CH₂CH₂OH.
 8. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹ is CH₂OH.9. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is CHF₂.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is selected fromethyl, CH(CH₃)CH₂OH, CH₂CH(CH₃)OH, CH(CH₃)CH₂CN, C(CH₃)₂CN, CH(CH₃)CN,C(CH₃)₂C(O)NH₂, CH₂C(O)N(CH₃)₂, and the following groups:


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R² is selected from ethyl, —(C₁₋₄ alkyl)-OH, —(C₁₋₃alkyl)-CN, (C₁₋₃ alkyl)-C(O)NH₂, —(C₁₋₄ alkyl)-C(O)N(CH₃)₂, andCH₂CH₂S(O)₂CH₃.
 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² i selected from the followinggroups:


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R² is selected from the following groups:


14. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R² is selected from the following groups:


15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein, R² is selected from the following groups:


16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein, R^(2A) is CH₃.
 17. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(2A) is selectedfrom C(O)CH₃, C(O)CH₂OCH₃, and C(O)CH₂OH.
 18. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R^(2B) isselected from CN, CF₃, and C(O)N(CH₃)₂.
 19. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein R^(2B) is H.
 20. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R^(2C) is F.
 21. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(2C) is H.
 22. The compound of claim1, having Formula IIa:

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1, having Formula IIb:

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim1, wherein the compound is selected from:(2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol;5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)nicotinonitrile;5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)picolinonitrile;4-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)picolinonitrile;(2-(2,6-Dichlorophenyl)-9-(1-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol;(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)phenyl)(morpholino)methanone;((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)methanone;1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzyl)piperazin-1-yl)-2-hydroxyethan-1-one;1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzyl)piperazin-1-yl)ethan-1-one;1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)piperazin-1-yl)-2-hydroxyethan-1-one;(2-(2-Chloro-6-methylphenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-][1,6]naphthyridin-3-yl)methanol;5-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)-N,N-dimethylpicolinamide;(3-(4-(2-(2,6-Dichlorophenyl)-3-methylimidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methyl-1H-1,2,3-triazol-4-yl)methanone;(3-(4-(2-(2,6-Dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(2-methyl-2H-tetrazol-5-yl)methanone;(2-(2,6-Dichlorophenyl)-9-(1-ethyl-1H-pyrazol-4-yl)imidazo[2,1-][1,6]naphthyridin-3-yl)methanol;2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile;2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile;1-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propan-2-ol;2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide;1-(4-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one;1-(4-(4-(2-(2-Chloro-6-methylphenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethan-1-one;1-(4-(2-(2-Chloro-6-methylphenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)butanenitrile;(R)-2-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propan-1-ol;(2-(2,6-Dichlorophenyl)-9-(1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol;3-(4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran1,1-dioxide;1-(3-((4-(2-(2,6-Dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)azetidin-1-yl)-2-methoxyethan-1-one;2-(2,6-Dichlorophenyl)-3-(difluoromethyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine;2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)acetonitrile;2-(2,6-Dichlorophenyl)-3-(difluoromethyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine;2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)ethan-1-ol;2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile;2-(4-(2-(2,6-Dichlorophenyl)-3-(difluoromethyl)imidazo[2,1-][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide;2-(2-(2,6-Dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)ethan-1-ol;and2-(2,6-Dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-][1,6]naphthyridin-3-amine,or a pharmaceutically salt of any of the aforementioned.
 25. Apharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 26. A method of inhibiting an FGFR3enzyme comprising contacting said enzyme with a compound of claim 1 or apharmaceutically acceptable salt thereof.
 27. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 28. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof in combination with anothertherapy or therapeutic agent.
 29. The method of claim 27, wherein saidcancer is selected from adenocarcinoma, bladder cancer, breast cancer,cervical cancer, cholangiocarcinoma, colorectal cancer, endometrialcancer, esophageal cancer, gall bladder cancer, gastric cancer, glioma,head and neck cancer, hepatocellular cancer, kidney cancer, livercancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, and Burkett's lymphoma.
 30. The method of claim 27, whereinsaid cancer is selected from adenocarcinoma, bladder cancer, breastcancer, cervical cancer, cholangiocarcinoma, endometrial cancer, gastriccancer, glioma, head and neck cancer, lung cancer, ovarian cancer,leukemia, and multiple myeloma.
 31. A method for treating a skeletal orchondrocyte disorder in a patient comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 32. The method of claim 31,wherein said skeletal or chondrocyte disorder is selected fromachrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia(TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndrome.